Novel compounds, their preparation and use

ABSTRACT

A novel class of dicarboxylic acid derivatives, the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be useful in the treatment and/or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR).

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. 119 of Danishapplication no. PA 2002 01966 filed Dec. 20, 2002 and U.S. applicationNo. 60/439,410 filed Jan. 10, 2003, the contents of which are fullyincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to novel dimeric dicarboxylic acidderivatives, to the use of these compounds as pharmaceuticalcompositions, to pharmaceutical compositions comprising the compoundsand to a method of treatment employing these compounds and compositions.More specifically, the compounds of the invention can be utilised in thetreatment and/or prevention of conditions mediated by the PeroxisomeProliferator-Activated Receptors (PPAR), in particular the PPARδsubtype.

BACKGROUND OF THE INVENTION

[0003] Coronary artery disease (CAD) is the major cause of death in Type2 diabetic and metabolic syndrome patients (i.e. patients that fallwithin the ‘deadly quartet’ category of impaired glucose tolerance,insulin resistance, hypertriglyceridaemia and/or obesity).

[0004] The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-lowering activitiesalthough they are neither potent nor efficacious enough to be a singletherapy of choice for the dyslipidaemia often observed in Type 2diabetic or metabolic syndrome patients. The thiazolidinediones alsopotently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content. Fibrates, on the one hand, are PPARα activators,acting primarily in the liver. Thiazolidinediones, on the other hand,are high affinity ligands for PPARγ acting primarily on adipose tissue.

[0005] Adipose tissue plays a central role in lipid homeostasis and themaintenance of energy balance in vertebrates. Adipocytes store energy inthe form of triglycerides during periods of nutritional affluence andrelease it in the form of free fatty acids at times of nutritionaldeprivation. The development of white adipose tissue is the result of acontinuous differentiation process throughout life. Much evidence pointsto the central role of PPARγ activation in initiating and regulatingthis cell differentiation. Several highly specialised proteins areinduced during adipocyte differentiation, most of them being involved inlipid storage and metabolism. The exact link from activation of PPARγ tochanges in glucose metabolism, most notably a decrease in insulinresistance in muscle, has not yet been clarified. A possible link is viafree fatty acids such that activation of PPARγ induces LipoproteinLipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoASynthetase (ACS) in adipose tissue but not in muscle tissue. This, inturn, reduces the concentration of free fatty acids in plasmadramatically, and due to substrate competition at the cellular level,skeletal muscle and other tissues with high metabolic rates eventuallyswitch from fatty acid oxidation to glucose oxidation with decreasedinsulin resistance as a consequence.

[0006] PPARα is involved in stimulating β-oxidation of fatty acids. Inrodents, a PPARα-mediated change in the expression of genes involved infatty acid metabolism lies at the basis of the phenomenon of peroxisomeproliferation, a pleiotropic cellular response, mainly limited to liverand kidney and which can lead to hepatocarcinogenesis in rodents. Thephenomenon of peroxisome proliferation is not seen in man. In additionto its role in peroxisome proliferation in rodents, PPARα is alsoinvolved in the control of HDL cholesterol levels in rodents and humans.This effect is, at least partially, based on a PPARα-mediatedtranscriptional regulation of the major HDL apolipoproteins, apo A-I andapo A-II. The hypotriglyceridemic action of fibrates and fatty acidsalso involves PPARα and can be summarised as follows: (I) an increasedlipolysis and clearance of remnant particles, due to changes inlipoprotein lipase and apo C-III levels, (II) a stimulation of cellularfatty acid uptake and their subsequent conversion to acyl-CoAderivatives by the induction of fatty acid binding protein and acyl-CoAsynthase, (III) an induction of fatty acid β-oxidation pathways, (IV) areduction in fatty acid and triglyceride synthesis, and finally (V) adecrease in VLDL production. Hence, both enhanced catabolism oftriglyceride-rich particles as well as reduced secretion of VLDLparticles constitutes mechanisms that contribute to the hypolipidemiceffect of fibrates.

[0007] PPARδ activation was initially reported not to be involved inmodulation of glucose or triglyceride levels. (Berger et al., j. Biol.Chem., 1999, Vol 274, pp. 6718-6725). Later it has been shown that PPAR8activation leads to increased levels of HDL cholesterol in dbldb mice(Leibowitz et al. FEBS letters 2000, 473, 333-336). Further, a PPARδagonist when dosed to insulin-resistant middle-aged obese rhesus monkeyscaused a dramitic dose-dependent rise in serum HDL cholesterol whilelowering the levels of small dense LDL, fasting triglycerides andfasting insulin (Oliver et al. PNAS 2001, 98, 5306-5311).The same paperalso showed that PPAR6 activation increased the reverse cholesteroltransporter ATP-binding cassette A1 and induced apolipoproteinA1-specific cholesterol efflux. The involvement of PPARδ in fatty acidoxidation in muscles was further substantiated in PPARα knock-out mice.Muoio et al. (J. Biol. Chem. 2002, 277, 26089-26097) showed that thehigh levels of PPARδ in skeletal muscle can compensate for deficiency inPPARα. Taken together these observations suggest that PPARδ activationis useful in the treatment and prevention of cardiovascular diseases andconditions including atherosclerosis, hypertriglyceridemia, and mixeddyslipidaemia (WO 01/00603).

[0008] A number of compounds have been reported to be useful in thetreatment of hyperglycemia, hyperlipidemia and hypercholesterolemia(U.S. Pat. No. 5,306,726, WO 91/19702, WO 95/03038, WO 96/04260, WO94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO 95/17394, WO99/08501, WO 99/19313, WO 99/16758 and WO 01/00603).

[0009] The following documents disclose various compounds with PPARγactivity: U.S. Pat. No. 5,063,240, EP 0597102, EP 0696585, WO 94/25448,JP 09291031, JP 08217766, WO 99/63983.

[0010] Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia.

[0011] This indicate that research for compounds displaying variousdegree of PPARα, PPARγ and PPARδ activation should lead to the discoveryof efficacious triglyceride and/or cholesterol and/or glucose loweringdrugs that have great potential in the treatment of diseases such astype 2 diabetes, dyslipidemia, syndrome X (including the metabolicsyndrome i.e. impaired glucose tolerance, insulin resistance,hypertrigyceridaemia and/or obesity), cardiovascular diseases (includingatherosclerosis) and hypercholesteremia.

[0012] Definitions

[0013] In the structural formulas given herein and throughout thepresent specification the following terms have the indicated meaning:

[0014] The terms “C_(1-n′)-alkyl” wherein n′ can be from 2 through 6, asused herein, represent a linear or branched, saturated hydrocarbon chainhaving the indicated number of carbon atoms. Examples of such groupsinclude, but are not limited to methyl, ethyl, n-propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,isohexyl and the like.

[0015] The term “C_(3-n′)-cycloalkyl” wherein n′ can be from 4 through6, as used herein, alone or in combination, represent a saturatedmonocyclic hydrocarbon group having the indicated number of carbonatoms. Examples of such groups include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0016] The terms “C_(1-n′)divalent saturated carbon chain” and“C_(1-n′)-alkylene” wherein n′ can be from 2 through 6, as used herein,represent a divalent linear or branched, saturated hydrocarbon chainhaving the indicated number of carbon atoms. Examples of such groupsinclude, but are not limited to methylene, ethylene, trimethylene,tetramethylene, propylene, ethylethylene, methylpropylene,ethylpropylene and the like.

[0017] The terms “C_(4-n′)-Cycloalkylene” wherein n′ can be from 5through 6, as used herein, represent a divalent saturated monocyclichydrocarbon group having the indicated number of carbon atoms. Examplesof such groups include, but are not limited to cyclopentylene,cyclohexylene and the like.

[0018] The term “C_(2-n′)-alkenyl” wherein n′ can be from 3 through 6,as used herein, represent an olefinically unsaturated branched orstraight hydrocarbon group having from 2 to the specified number ofcarbon atoms and at least one double bond. Examples of such groupsinclude, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl,iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.

[0019] The term “C_(2-n′)-alkenylene” wherein n′ can be from 3 through6, as used herein, represent an divalent olefinically unsaturatedbranched or straight hydrocarbon group having from 2 to the specifiednumber of carbon atoms and at least one double bond. Examples of suchgroups include, but are not limited to ethenylene (—CH═CH—), thepropenylene isomers (e.g., —CH₂CH∇CH— and —C(CH₃)═CH—), the butenyleneisomers (e.g., —CH₂CH═C(CH₃)—and —CH₂CH₂CH═CH—) and the like.

[0020] The terms “C_(4-n′)-alkenynyl” as used herein, represent anunsaturated branched or straight hydrocarbon group having from 4 to thespecified number of carbon atoms and both at least one double bond andat least one triple bond. Examples of such groups include, but are notlimited to, 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and thelike, especially preferred is 1-pentene-4-yne.

[0021] The term “C_(4-n′)-cycloalkenylene” wherein n′ can be from 5through 6, as used herein, represent an divalent unsaturated monocyclichydrocarbon group having from 4 to the specified number of carbon atomsand at least one double bond. Examples of such groups include, but arenot limited to cyclohexenylene and the like.

[0022] The term “C_(3-n′)-alkynyl” wherein n′ can be from 4 through 6,as used herein, represent an unsaturated branched or straighthydrocarbon group having from 2 to the specified number of carbon atomsand at least one triple bond. Examples of such groups include, but arenot limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,1-pentynyl, 2-pentynyl and the like.

[0023] The term “C_(2-n′)-alkynylene′ wherein n′ can be from 3 through6, as used herein, represent an divalent unsaturated branched orstraight hydrocarbon group having from 2 to the specified number ofcarbon atoms and at least one triple bond. Examples of such groupsinclude, but are not limited to, propynylene (—CH₂C≡C—), the butynyleneisomers (e.g., —CH₂CH₂C≡C—, —CH₂C≡C—CH₂—), and the like.

[0024] The term “C_(4-n′)-alkenynylene” wherein n′ can be from 5 through9 as used herein, represent an divalent unsaturated branched or straighthydrocarbon group having from 4 to the specified number of carbon atomsand both at least one double bond and at least one triple bond. Examplesof such groups include, but are not limited to, 1-penten-4-ynylene,3-penten-1-ynylene, 1,3-hexadiene-5-ynylene and the like.

[0025] The term “C_(3-n′)-divalent unsaturated carbon chain” wherein n′can be from 4 through 9, as used herein, represent an divalentunsaturated branched or straight hydrocarbon group having from 3 to thespecified number of carbon atoms and at least one double bound(alkenylen) or at least one triple bound (alkynylene) or a combinationhereof (alkenynylene). Examples of such groups include, but are notlimited to ethenylene (—CH═CH—), the propenylene isomers (e.g.,—CH₂CH═CH— and —C(CH₃)═CH—), the butenylene isomers (e.g.,—CH₂CH═C(CH₃)— and CH₂CH₂CH═CH—), propynylene (—CH₂C≡C—), the butynyleneisomers (e.g., —CH₂CH₂C≡C—, —CH₂C≡C—CH₂—), 1-penten-4-ynylene,3-penten-1-ynylene, 1,3-hexadiene-5-ynylene and the like.

[0026] The term “C_(1-n′)-alkoxy” wherein n′ can be from 2 through 6, asused herein, alone or in combination, refers to a straight or branchedconfiguration linked through an ether oxygen having its free valencebond from the ether oxygen. Examples of such linear alkoxy groupsinclude, but are not limited to methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy and the like. Examples of such branched alkoxy include,but are not limited to isopropoxy, sec-butoxy, tert-butoxy,isopentyloxy, isohexyloxy and the like.

[0027] The term “C_(3-n′)-Cycloalkoxy” wherein n′ can be from 4 through6, as used herein, alone or in combination, represent a saturatedmonocyclic hydrocarbon group having the indicated number of carbon atomslinked through an ether oxygen having its free valence bond from theether oxygen. Examples of such cycloalkoxy groups include, but are notlimited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxyand the like.

[0028] The term “C_(1-n′)-alkylthio” wherein n′ can be from 2 through 6,as used herein, alone or in combination, refers to a straight orbranched monovalent substituent comprising a C₁₋₆-alkyl group linkedthrough a divalent sulfur atom having its free valence bond from thesulfur atom and having 1 to 6 carbon atoms. Examples of such groupsinclude, but are not limited to methylthio, ethylthio, propylthio,butylthio, pentylthio and the like.

[0029] The term “C_(3-n′)-cycloalkylthio” wherein n′ can be from 4through 6, as used herein, alone or in combination, represent asaturated monocyclic hydrocarbon group having the indicated number ofcarbon atoms linked through a divalent sulfur atom having its freevalence bond from the sulfur atom. Examples of such cycloalkoxy groupsinclude, but are not limited to cyclopropylthio, cyclobutylthio,cyclopentylthio, cyclohexylthio and the like.

[0030] The term “aryl” as used herein refers to an aromatic monocyclicor an aromatic fused bi- or tricyclic hydrocarbon group. Examples ofsuch groups include, but are not limited to phenyl, naphthyl,anthracenyl, phenanthrenyl, azulenyl, fluorenyl and the like.

[0031] The term “arylene” as used herein refers to divalent aromaticmonocyclic or a divalent aromatic fused bi- or tricyclic hydrocarbongroup (derived from aryl). Examples of such groups include, but are notlimited to phenylene, naphthylene, fluorenylene and the like.

[0032] The term “heteroaryl” as used herein, alone or in combination,refers to a divalent substituent comprising a 5-7 membered monocyclicaromatic system or a 8-10 membered bicyclic fused aromatic systemcontaining one or more heteroatoms selected from nitrogen, oxygen andsulfur or a 10-16 membered tricyclic fused aromatic system containingone or more heteroatoms selected from nitrogen, oxygen and sulfur e.g.furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, quinazolinyl,quinoxalinnyl, indolyl, benzimidazolyl, benzofuranyl, pteridinyl,purinyl, carbazolyl, β-carbolinyl, acridinyl, phenanthrolinyl,phenazinyl, phenoxazinyl, phenothiazinyl and the like The term“heteroarylene” as used herein, alone or in combination, refers to adivalent substituent (derived from heteroaryl) comprising a 5-7 memberedmonocyclic aromatic system or a 8-10 membered bicyclic aromatic systemcontaining one or more heteroatoms selected from nitrogen, oxygen andsulfur or a 10-16 membered tricyclic fused aromatic system containingone or more heteroatoms selected from nitrogen, oxygen and sulfur e.g.furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene,triazolylene, pyrazinylene, pyrimidinylene, pyridazinylene,isothiazolylene, isoxazolylene, oxazolylene, oxadiazolylene,thiadiazolylene, quinolylene, isoquinolylene, quinazolinylene,quinoxalinnylene, indolylene, benzimidazolylene, benzofuranylene,pteridinylene, purinylene carbazolylene, β-carbolinylene, acridinylene,phenanthrolinylene, phenazinylene, phenoxazinylene, phenothiazinyleneand the like.

[0033] The term “a divalent polycyclic ringsystem” as used herein refersto a divalent group formed from a polycyclic ringsystem containingindenpending of each other 2 trough 4 aryl or heteroaryl ring systemsjoined by single bonds. Example of such bi-, ter- and quaterarylylenehaving 2 through 4 identical aryl ring systems include, but are notlimited to biphenylylene, binaphthylylene, terphenylylene,temaphthylylene, quaterphenylylene, quatemaphthylylene and the like.Example of such bi-, ter- and quaterheteroarylylene having 2 through 4identical heteroaryl ring systems include, but are not limited tobipyridylylene, biindolylylene, terpyridylylene, terindolylylene,quaterpyridylylene, quaterindolylylene and the like. Example of suchpolycyclic ringsystems having non identical ring systems include, butare not limited to diphenylpyridine and the like.

[0034] The term “aralkoxy” as used herein refers to a C₁₋₆-alkoxy groupsubstituted with an aromatic carbohydride, such as benzyloxy,phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy andthe like.

[0035] The term “aralkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with an aromatic carbohydride; such as benzyl, phenethyl,3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like.

[0036] The term “halogen” means fluorine, chlorine, bromine or iodine.

[0037] The term “treatment” as used herein includes treatment,prevention and management of conditions mediated by PeroxisomeProliferator-Activated Receptors (PPAR).

[0038] Certain of the above defined terms may occur more than once inthe structural formulae, and upon such occurrence each term shall bedefined independently of the other.

[0039] The term “optionally substituted” as used herein means that thegroups in question are either unsubstituted or substituted with one ormore of the substituents specified. When the groups in question aresubstituted with more than one substituent the substituents may be thesame or different.

DESCRIPTION OF THE INVENTION

[0040] The present invention relates to compounds of the general formula(I):

[0041] wherein A is C₁₋₃-alkylene which is optionally substituted withone or more substituents selected from

[0042] halogen or

[0043] C₁₋₃-alkyl, C₁₋₆alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆alkylthio,C₃₋₆-cycloalkylthio or aralkoxy each of which is optionally substitutedwith one or more halogens; or

[0044] NR₁R₂ wherein R₁ represents hydrogen or C₁₋₃-alkyl and R₂represents —R₃—(C═O)—R₄ wherein:

[0045] R₃ represents C₁₋₆alkylene, C₂₋₄-alkenylene, C₄₋₄-cycloalkylene,C₄₋₄-cycloalkenylene, or arylene optionally substituted with one or morehalogens;

[0046] R₄ represents aryl optionally substituted with one or morehalogens; or

[0047] A is —O -A′ or —S-A′ wherein —O— or —S— is linked to X in formula(I) and wherein A′ is C₁₋₃-alkylene which is optionally substituted withone or more substituents selected from

[0048] halogen or

[0049] C₁₋₃-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆alkylthio,C₃₋₆-cycloalkylthio or aralkoxy each of which is optionally substitutedwith one or more halogens; or

[0050] NR₁R₂ wherein R₁ represents hydrogen or C₁₋₃-alkyl and R₂represents —R₃—(C═O)-R₄ wherein:

[0051] R₃ represents C₁₋₆alkylene, C₂₋₆-alkenylene, C₄₋₆-cycloalkylene,C₄₋₆-cycloalkenylene, or arylene optionally substituted with one or morehalogens;

[0052] R₄ represents aryl optionally substituted with one or morehalogens; and

[0053] B is C₁₋₃-alkylene which is optionally substituted with one ormore substituents selected from

[0054] halogen or

[0055] C₁₋₃-alkyl, C₁₋₆alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio,C₃₋₆-cycloalkylthio or aralkoxy each of which is optionally substitutedwith one or more halogens; or

[0056] NR₁R₂wherein R₁ represents hydrogen or C₁₋₃-alkyl and R₂represents —R₃—(C═O)—R₄ wherein:

[0057] R₃ represents C₁₋₆-alkylene, C₂₋₆-alkenylene, C₄₋₆-cycloalkylene,C₄₋₆-cycloalkenylene, or arylene optionally substituted with one or morehalogens;

[0058] R₄ represents aryl optionally substituted with one or morehalogens; or

[0059] B is —O—B′ or —S—B′ wherein —O— or —S— is linked to Y in formula(I) and wherein B′ is C₁₋₃-alkylene which is optionally substituted withone or more substituents selected from

[0060] halogen or

[0061] C₁₋₃-alkyl, C₁₋₆alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆alkylthio,C₃₋₆-cycloalkylthio or aralkoxy each of which is optionally substitutedwith one or more halogens; or

[0062] NR₁R₂ wherein R₁ represents hydrogen or C₁₋₃-alkyl and R₂represents —R₃—(C═O)—R₄ wherein:

[0063] R₃ represents C₁₋₆alkylene, C₂₋₆-alkenylene, C₄₋₆-cycloalkylene,C₄₋₆-cycloalkenylene, or arylene optionally substituted with one or morehalogens;

[0064] R₄ represents aryl optionally substituted with one or morehalogens; and

[0065] D is H, C₁₋₆alkyl or C₃₋₆-cycloalkyl; and

[0066] E is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl; and

[0067] L and M are independently —O— or —S—; and

[0068] T is C₁₋₆divalent saturated carbon chain optionally substitutedwith one or more substituents selected from

[0069] halogen or hydroxy; or

[0070] aryl, aralkoxy or C₁₋₃-alkoxy which is optionally substitutedwith halogen; or

[0071] T is —NR₁-T′ wherein —NR₁— is linked to Z in formula (I) andwherein T′ is C₁₋₆ alkylene which is optionally substituted with one ormore halogen and R₁ represents hydrogen or C₁₋₃ alkyl; and

[0072] U is C₁₋₆ divalent saturated carbon chain optionally substitutedwith one or more substituents selected from

[0073] halogen or hydroxy; or

[0074] aryl, aralkoxy or C₁₋₃-alkoxy which is optionally substitutedwith halogen; or

[0075] U is —NR₁-U′ wherein —NR₁— is linked to Z in formula (I) andwherein U′ is C₁₋₆ alkylene which is optionally substituted with one ormore halogen and R₁ represents hydrogen or C₁₋₃ alkyl; and

[0076] X is arylene or heteroarylene each of which is optionallysubstituted with one or more substituents selected from

[0077] halogen or hydroxy; or

[0078] C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,C₁₋₆alkylthio, C₃₋₆-cycloalkylthio, aryl, aralkyl each of which isoptionally substituted with one or more halogen; and

[0079] Y is arylene or heteroarylene each of which is optionallysubstituted with one or more substituents selected from

[0080] halogen or hydroxy; or

[0081] C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,C₁₋₆alkylthio, C₃₋₆-cycloalkylthio, aryl, aralkyl each of which isoptionally substituted with one or more halogen; and

[0082] Z is arylene, heteroarylene or a divalent polycyclic ringsystemeach of which is optionally substituted with one or more substituentsselected from

[0083] halogen, oxo or hydroxy; or

[0084] C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,C₁₋₆alkylthio, C₃₋₆-cycloalkylthio each of which is optionallysubstituted with one or more halogen; or

[0085] a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, or any tautomeric forms, stereoisomers,mixture of stereoisomers including a racemic mixture, or polymorphs.

[0086] In one embodiment, the present invention is concerned withcompounds of formula (I) wherein A is C₁₋₃-alkylene which is optionallysubstituted with one or more substituents selected from

[0087] methyl, C₁₋₃-alkoxy, C₃₋₆-cycloalkoxy or benzyloxy each of whichis optionally substituted with one or more halogen; or

[0088] NR₁R₂wherein R₁ represents hydrogen and R₂ represents—R₃—(C═O)—R₄ wherein:

[0089] R₃ represents C₁₋₆-alkylene, C₂₋₆-alkenylene, C₄₋₆-cycloalkylene,C₄₋₆-cycloalkenylene, or phenylene optionally substituted with one ormore halogens;

[0090] R₄ represents phenyl optionally substituted with one or morehalogens.

[0091] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein A is methylene or ethylene each ofwhich is optionally substituted with one or more substituents selectedfrom

[0092] methoxy or ethoxy; or

[0093] NR₁R₂wherein R₁ represents hydrogen and R₂ represents—R₃—(C═O)—R₄ wherein R₃ and R4 represents phenyl.

[0094] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein A is ethylene which is optionallysubstituted with ethoxy.

[0095] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein A is —O-A′ or —S-A′ wherein —O— or —S—is linked to X in formula (I) and wherein A′ is C₁₋₃-alkylene which isoptionally substituted with one or more substituents selected from

[0096] halogen or

[0097] C₁₋₃-alkyl, C₁₋₆alkoxy, C₃₋₆-cycloalkoxy or aralkoxy each ofwhich is optionally substituted with halogen.

[0098] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein A is —O-A′ or —S-A′ wherein —O— or —S—is linked to X in formula (I) and wherein A′ is methylene or ethyleneeach of which is optionally substituted with one or more substituentsselected from methyl, methoxy or ethoxy.

[0099] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein A is —O-A′ wherein —O— or is linked toX in formula (I) and wherein A′ is methylene or ethylene.

[0100] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein B is C₁₋₃-alkylene, which is optionallysubstituted with one or more substituents selected from

[0101] methyl, C₁₋₃-alkoxy, C₃₋₆-cycloalkoxy or benzyloxy each of whichis optionally substituted with one or more halogen; or

[0102] NR₁R₂wherein R₁ represents hydrogen and R₂ represents—R₃—(C═O)—R₄ wherein:

[0103] R₃ represents C₁₋₆alkylene, C₂₋₆-alkenylene, C₄₋₆-cycloalkylene,C₄₋₆-cycloalkenylene, or phenylene optionally substituted with one ormore halogens;

[0104] R₄ represents phenyl optionally substituted with one or morehalogens.

[0105] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein B is methylene or ethylene each ofwhich is optionally substituted with one or more substituents selectedfrom

[0106] methoxy or ethoxy; or

[0107] NR₁R₂ wherein R₁ represents hydrogen and R₂ represents—R₃—(C═O)—R₄ wherein R₃ and R4 represents phenyl.

[0108] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein B is ethylene which is optionallysubstituted with ethoxy.

[0109] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein B is —O— B′ or —S—B′ wherein —O— or —S—is linked to Y in formula (I) and wherein B′ is C₁₋₃-alkylene which isoptionally substituted with one or more substituents selected from

[0110] halogen or

[0111] C₁₋₃-alkyl, C₁₋₆alkoxy, C₃₋₆-cycloalkoxy or aralkoxy each ofwhich is optionally substituted with halogen.

[0112] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein B is —O— B′ or —S=13 B′ wherein —O— or—S— is linked to Y in formula (I) and wherein B′ is methylene orethylene each of which is optionally substituted with one or moresubstituents selected from methyl, methoxy or ethoxy.

[0113] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein B is —O— B′ wherein —O— is linked to Yin formula (I) and wherein B′ is methylene or ethylene.

[0114] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein D is H.

[0115] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein D is methyl.

[0116] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein D is ethyl.

[0117] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein D is isopropyl.

[0118] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein E is H.

[0119] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein E is methyl.

[0120] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein E is ethyl.

[0121] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein E is isopropyl.

[0122] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein L is —O—.

[0123] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein L is —S—.

[0124] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein M is —O—.

[0125] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein M is —S—.

[0126] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is C₁₋₆ divalent saturated carbonchain optionally substituted with one or more substituents selected fromphenyl, benzyloxy or C₁₋₃-alkoxy which is optionally substituted withhalogen.

[0127] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is an unsubstituted C₁₋₆ divalentsaturated carbon chain.

[0128] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is methylene.

[0129] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is ethylene.

[0130] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is propylene.

[0131] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is —NR₁-T′ wherein —NR₁— is linked toZ in formula (I) and wherein T′ is C₁₋₆ alkylene which is optionallysubstituted with one or more halogen and R₁ represents hydrogen or C₁₋₃alkyl.

[0132] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is —NR₁-T′ wherein —NR₁— is linked toZ in formula (I) and wherein T′ is C₁₋₃ alkylene and R₁ representshydrogen or C₁₋₃ alkyl.

[0133] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein T is —NR₁-T′ wherein —NR₁— is linked toZ in formula (I) and wherein T′ is ethylene and R₁ is methyl.

[0134] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is C₁₋₆divalent saturated carbonchain optionally substituted with one or more substituents selected fromphenyl, benzyloxy or C₁₋₃-alkoxy which is optionally substituted withhalogen.

[0135] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is an unsubstituted C₁₋₆divalentsaturated carbon chain.

[0136] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is methylene.

[0137] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is ethylene.

[0138] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is propylene.

[0139] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is —NR₁—U′ wherein -—R₁— is linked toZ in formula (I) and wherein U′ is C₁₋₆ alkylene which is optionallysubstituted with one or more halogen and R₁ represents hydrogen or C₁₋₃alkyl.

[0140] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is —NR₁—U′ wherein —NR₁— is linked toZ in formula (I) and wherein U′ is C₁₋₃ alkylene and R₁ representshydrogen or C₁₋₃ alkyl.

[0141] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein U is —NR₁—U′ wherein —NR₁— is linked toZ in formula (I) and wherein U′ is ethylene and R₁ is methyl.

[0142] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein X is arylene or heteroarylene each ofwhich is optionally substituted with one or more substituents selectedfrom

[0143] halogen; or

[0144] C₁₋₆alkyl, aryl each of which is optionally substituted with oneor more halogen.

[0145] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein X is arylene optionally substitutedwith one or more substituents selected from

[0146] halogen; or

[0147] C₁₋₆alkyl, aryl each of which is optionally substituted with oneor more halogen.

[0148] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein X is phenylene optionally substitutedwith one or more substituents selected from

[0149] halogen; or

[0150] C₁₋₃-alkyl, phenyl each of which is optionally substituted withone or more halogen.

[0151] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein X is phenylene optionally substitutedwith one or more halogen, methyl or phenyl.

[0152] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein X is phenylene optionally substitutedwith one or more trifluoromethyl or methoxy.

[0153] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Y is arylene or heteroarylene each ofwhich is optionally substituted with one or more substituents selectedfrom

[0154] halogen; or

[0155] C₁₋₆-alkyl, aryl each of which is optionally substituted with oneor more halogen.

[0156] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Y is arylene optionally substitutedwith one or more substituents selected from

[0157] halogen; or

[0158] C₁₋₆alkyl, aryl each of which is optionally substituted with oneor more halogen.

[0159] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Y is phenylene optionally substitutedwith one or more substituents selected from

[0160] halogen; or

[0161] C₁₋₃-alkyl, phenyl each of which is optionally substituted withone or more halogen.

[0162] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Y is phenylene optionally substitutedwith one or more halogen, methyl or phenyl.

[0163] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Y is phenylene optionally substitutedwith one or more trifluoromethyl or methoxy.

[0164] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is arylene, heteroarylene or adivalent polycyclic ringsystem each of which is optionally substitutedwith one or more substituents selected from

[0165] halogen, oxo; or

[0166] C₁₋₆alkyl, C₁₋₆alkoxy each of which is optionally substitutedwith one or more halogen.

[0167] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is selected among the followinggroups:

[0168] which is optionally substituted with one or more substituentsselected from

[0169] halogen or

[0170] C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionally substitutedwith one or more halogen.

[0171] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is selected among the followinggroups:

[0172] which is optionally substituted with one or more substituentsselected from

[0173] halogen or

[0174] C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionally substitutedwith one or more halogen.

[0175] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is selected among the followinggroups:

[0176] which is optionally substituted with one or more substituentsselected from

[0177] halogen or

[0178] C₁₋₆alkyl or C₁₋₆-alkoxy each of which is optionally substitutedwith one or more halogen.

[0179] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is selected among the followinggroups:

[0180] which is optionally substituted with one or more substituentsselected from

[0181] halogen or

[0182] C₁₋₆alkyl or C₁₋₆alkoxy each of which is optionally substitutedwith one or more halogen.

[0183] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is:

[0184] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is:

[0185] which is optionally substituted with one or more oftrifluoromethyl.

[0186] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is:

[0187] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is:

[0188] In another embodiment, the present invention is concerned withcompounds of formula (I) wherein Z is:

[0189] In another embodiment, the present invention is concerned withcompounds of the present invention having a (S)-configuration whenpossible.

[0190] In another embodiment, the present invention is concerned withcompounds of the present invention which is a mixed PPARα/PPARγ profile.

[0191] In another embodiment, the present invention is concerned withcompounds of the present invention which is a mixed PPARα/PPARδ profile.

[0192] In another embodiment, the present invention is concerned withcompounds of the present invention which is a mixed PPARγ/PPARδ profile.

[0193] In another embodiment, the present invention is concerned withcompounds of the present invention which is a mixed PPARαPPARγ/PPARδprofile.

[0194] In another embodiment, the present invention is concerned withcompounds of the present invention, which is a selective PPARα profile.

[0195] In another embodiment, the present invention is concerned withcompounds of the present invention, which is a selective PPARγ profile.

[0196] In another embodiment, the present invention is concerned withcompounds of the present invention, which is a selective PPARδ profile.

[0197] Examples of specific compounds of the invention are:

[0198]2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-methoxycarbonyl-ethyl)-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-phenyl]-propionicacid;

[0199]3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-2-chloro-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-3-chloro-phenyl]-2-ethoxy-propionicacid;

[0200](5′-{2-[(6-{[2-(2′-Ethoxycarbonylmethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-acetic acid;

[0201](5′-{2-[(6-{[2-(2′-Carboxymethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid;

[0202](S,S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamio)-2-methoxycarbonyl-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-propionicacid;

[0203](S,S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-carboxy-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-propionicacid;

[0204](3-Chloro-4-{2-[(6-{[2-(2-chloro-4-ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino)-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid;

[0205](4-{2-[(6-{[2-(4-Carboxymethyl-2-chloro-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-3-chloro-phenyl)-aceticacid;

[0206](3-{2-[(6-{[2-(3-Ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-ylmethyl-amino]-ethoxy}-phenyl)-acetic acid;

[0207](3-{2-[(6-{[2-(3-Carboxymethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid;

[0208](S,S)-2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-propionicacid;

[0209](S,S)-3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-2-ethoxy-propionicacid;

[0210](S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid;

[0211](S,S)-3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0212](S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid;

[0213](S,S)-3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0214](S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0215] (S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0216](S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0217](S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0218](S,S)-3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid isopropyl ester;

[0219](S,S)-3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0220](S,S)-2-Ethoxy-3-{4-[3-(7-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-propionicacid isopropyl ester;

[0221](S,S)-3-{4-[3-(7-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2yl)-propoxy]-phenyl}-1-ethoxy-propionicacid;

[0222][4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoro-methyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[0223][4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoro-methyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[0224][4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[0225][4-(3-{7-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propylsulfanyl)-2-methyl-phenoxy]-acetic acid;

[0226][4-(3-(7-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl)-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[0227](4-{2-[2-(3-{4-[2-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;

[0228](4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;

[0229](S,S)-2-Ethoxy-3-[4-(2-{2-[4′-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid;

[0230] (S,S)-3-[4-(2-{2-[4′-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid;

[0231](S,S)-2-Ethoxy-3-[4-(2-{2-[3-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid;

[0232](S,S)-3-[4-(2-{2-[3-(4-(2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid; or

[0233] a salt thereof with a pharmaceutically acceptable acid or base,or any optical isomer or mixture of optical isomers, including a racemicmixture, or any tautomeric forms.

[0234] Other examples of specific compounds of the invention are:

[0235][4-(3-{4′-[3-(4-Carboxymethylsulfanyl-3-chloro-phenylsulfanyl)-propyl]-3,3′-bis-rifluoromethyl-biphenyl-4-yl)-propylsulfanyl)-2-chloro-phenylsulfanyl]-aceticacid;

[0236][4-[3-[4′-[3-(4-Carboxymethoxy-3-trifluoromethylphenylsulfanyl)propyl]biphenyl-4-yl]-propyl-sulfanyl]-2-trifluoromethylphenoxy]aceticacid;

[0237][4-[3-[4′-[3-(4-Carboxymethoxy-3-chlorophenylsulfanyl)propyl]-3,3′-bis-trifluoromethylbiphenyl-4-yl]propylsulfanyl]-2-chlorophenoxy]aceticacid;

[0238][4-(3-{4′-[3-(4-Carboxymethoxy-3-chloro-phenylsulfanyl)-propyl]-biphenyl-4-yl}-propyl-sulfanyl)-2-chloro-phenoxy]-aceticacid;

[0239][4-(3-{4′-[3-(4-Carboxymethoxy-3-methoxy-phenylsulfanyl)-propyl]-biphenyl-4-yl}-propyl-sulfanyl)-2-methoxy-phenoxy]-aceticacid;

[0240]{4-[3-(4-{4-[3-(4-Carboxymethoxy-3-trifluoromethyl-phenylsulfanyl)-propyl]-2-trifluoromethyl-phenylsulfanyl}-3-trifluoromethyl-phenyl)-propylsulfanyl]-2-trifluoromethyl-phenoxy}-aceticacid; or

[0241] a salt thereof with a pharmaceutically acceptable acid or base,or any optical isomer or mixture of optical isomers, including a racemicmixture, or any tautomeric forms.

[0242] Other examples of specific compounds of the invention are:

[0243]3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}ethoxy)-phenyl]-2-ethoxy-propionicacid;

[0244](3-{2-[(6-{[2-(3-Carboxymethyl-phenoxy)-ethyl]-methyl-amino}pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid;

[0245]2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-carboxy-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-propionicacid;

[0246](5′-{2-[(6-{[2-(2′-Carboxymethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid;

[0247]3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-phenyl]-2-ethoxy-propionicacid;

[0248](4-{2-[(6-{[2-(4-Carboxymethyl-2-chloro-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-3-chloro-phenyl)-aceticacid;

[0249](4-{2-[(6-{[2-(4-Carboxymethyl-2-bromo-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-3-bromo-phenyl)-aceticacid;

[0250](4-{2-[(6-{[2-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;

[0251](4-{2-[(6-{[2-(4-Carboxymethoxy-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-phenoxy)-aceticacid;

[0252](3-{2-[(6-{[2-(3-Carboxymethyl-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-phenyl)-aceticacid;

[0253](4-{2-[(6-{[2-(4-Carboxymethyl-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-phenyl)-aceticacid;

[0254]2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-carboxy-ethyl]-phenylsulfanyl}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethylsulfanyl]-phenyl}-propionicacid;

[0255]3-{4-[2-({6-[(2-{4-[2-Carboxy-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-ethyl]-phenyl-sulfanyl}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethylsulfanyl]-phenyl}-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionicacid;

[0256] 3-{4-[2-({6-[(2-{4-[2-Carboxy-2-( 1-methyl-3-oxo-3-phenyl-propenylamino)-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionicacid;

[0257](4-{2-[(6-{[2-(4-Carboxymethyl-2-chloro-phenylsufanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-3-chloro-phenyl)-aceticacid;

[0258](4-{2-[(6-{[2-(4-Carboxymethyl-2-bromo-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-3-bromo-phenyl)-aceticacid;

[0259]3-[4-(2-{2-[3-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2yl)-phenyl]-5-methyl-oxazol-4-yl)-ethoxy)-phenyl]-2-ethoxy-propionicacid;

[0260](4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-3-methyl-phenylsufanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;

[0261](4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-3-methyl-phenoxy)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid;

[0262](4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-phenoxy)-aceticacid;

[0263](4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-phenoxy)-aceticacid;

[0264]3-[4-(2-{2-[3-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethylsulfanyl)-phenyl]-2-ethoxy-propionicacid;

[0265]3-{4-[3-(7-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxyl]-phenyl}-2-ethoxy-propionicacid;

[0266]3-{4-[3-(7-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-propyl)-9H-fluoren-2-yl)-propylsulfanyl]-phenyl}-2-ethoxy-propionicacid;

[0267][4-(3-{7-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl)-propyl-sulfanyl)-2-methyl-phenoxy]-aceticacid;

[0268][4-(3-{7-[3-(4-Carboxymethoxy-phenylsulfanyl)-propyl]-9H-fluoren-2-yl)-propylsulfanyl)-phenoxy]-aceticacid;

[0269]3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0270]3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-propyl}-9H-fluoren-2-yl)-propylsulfanyl]-phenyl}-2-ethoxy-propionicacid;

[0271]3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0272]3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0273]3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0274]3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;

[0275][4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[0276][4-(3-{4′-[3-(4-Carboxymethoxy-phenylsulfanylypropyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-phenoxy]-aceticacid;

[0277][4-(3-{4′-[3-(4-Carboxymethoxy-phenoxy)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propoxy)-phenoxy]-aceticacid;

[0278][4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenoxy)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propoxy)-2-methyl-phenoxy]-aceticacid;

[0279][4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[0280][4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenoxy)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propoxy)-2-methyl-phenoxy]-aceticacid;

[0281]3-[4-(2-{2-[4′-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid; or

[0282] a salt thereof with a pharmaceutically acceptable acid or base,or any optical isomer or mixture of optical isomers, including a racemicmixture, or any tautomeric forms.

[0283] The present invention also encompasses pharmaceuticallyacceptable salts of the present compounds. Such salts includepharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable base addition salts, pharmaceutically acceptable metal salts,ammonium and alkylated ammonium salts. Acid addition salts include saltsof inorganic acids as well as organic acids. Representative examples ofsuitable inorganic acids include hydrochloric, hydrobromic, hydroiodic,phosphoric, sulfuric, nitric acids and the like. Representative examplesof suitable organic acids include formic, acetic, trichloroacetic,trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric,pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic,citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic,glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci. 1977, 66, 2, which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,magnesium, zinc, calcium salts and the like. Examples of amines andorganic amines include ammonium, methylamine, dimethylamine,trimethylamine, ethylamine, diethylamine, propylamine, butylamine,tetramethylamine, ethanolamine, diethanolamine, triethanolamine,meglumine, ethylenediamine, choline, N,N′-dibenzylethylenediamine,N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the like.Examples of cationic amino acids include lysine, arginine, histidine andthe like.

[0284] The pharmaceutically acceptable salts are prepared by reactingthe present compound with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, magnesium hydroxide and the like, in solvents likeether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.Mixture of solvents may be used. Organic bases like lysine, arginine,diethanolamine, choline, guandine and their derivatives etc. may also beused. Alternatively, acid addition salts wherever applicable areprepared by treatment with acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonicacid, methanesulfonic acid, acetic acid, citric acid, maleic acidsalicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid,succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and thelike in solvents like ethyl acetate, ether, alcohols, acetone, THF,dioxane etc. Mixture of solvents may also be used.

[0285] The stereoisomers of the compounds forming part of this inventionmay be prepared by using reactants in their single enantiomeric form inthe process wherever possible or by conducting the reaction in thepresence of reagents or catalysts in their single enantiomer form or byresolving the mixture of stereoisomers by conventional methods. Some ofthe preferred methods include use of microbial resolution, enzymaticresolution, resolving the diastereomeric salts formed with chiral acidssuch as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid,and the like wherever applicable or chiral bases such as brucine, (R)-or (S)-phenylethylamine, cinchona alkaloids and their derivatives andthe like. Commonly used methods are compiled by Jaques et al in“Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). Morespecifically the present compound may be converted to a 1:1 mixture ofdiastereomeric amides by treating with chiral amines, aminoacids,aminoalcohols derived from aminoacids; conventional reaction conditionsmay be employed to convert acid into an amide; the dia-stereomers may beseparated either by fractional crystallization or chromatography and thestereoisomers of the compound of the present invnetion may be preparedby hydrolysing the pure diastereomeric amide.

[0286] Various polymorphs of compound of the present invention formingpart of this invention may be prepared by crystallization of compound ofthe invention under different conditions. For example, using differentsolvents commonly used or their mixtures for recrystallization;crystallizations at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallizations.Polymorphs may also be obtained by heating or melting the compoundfollowed by gradual or fast cooling. The presence of polymorphs may bedetermined by solid probe nmr spectroscopy, ir spectroscopy,differential scanning calorimetry, powder X-ray diffraction or suchother techniques.

[0287] The invention also encompasses prodrugs of the present compounds,which on administration undergo chemical conversion by metabolicprocesses before becoming active pharmacological substances. In general,such prodrugs will be functional derivatives of the present compounds,which are readily convertible in vivo into the required compound of thethe present invention. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0288] The invention also encompasses active metabolites of the presentcompounds.

[0289] The invention also relates to pharmaceutical compositionscomprising, as an active ingredient, at least one compound of thepresent invention or any optical or geometric isomer or tautomeric formthereof including mixtures of these or a pharmaceutically acceptablesalt thereof together with one or more pharmaceutically acceptablecarriers or diluents.

[0290] Furthermore, the invention relates to the use of compounds of thepresent invention or their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts or pharmaceuticallyacceptable solvates thereof for the preparation of a pharmaceuticalcomposition for the treatment and/or prevention of conditions mediatedby nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR) such as the conditions mentionedabove.

[0291] In another aspect, the present invention relates to a method oftreating and/or preventing Type I or Type II diabetes.

[0292] In a still further aspect, the present invention relates to theuse of one or more compounds of the present invention orpharmaceutically acceptable salts thereof for the preparation of apharmaceutical composition for the treatment and/or prevention of Type Ior Type II diabetes.

[0293] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of IGT.

[0294] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of Type 2 diabetes.

[0295] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from IGT to Type 2diabetes.

[0296] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

[0297] In another aspect, the present compounds reduce blood glucose andtriglyceride levels and are accordingly useful for the treatment and/orprevention of ailments and disorders such as diabetes and/or obesity.

[0298] In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of insulin resistance (Type 2 diabetes),impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX such as hypertension, obesity, insulin resistance, hyperglycaemia,atherosclerosis, hyperlipidemia, coronary artery disease, myocardialischemia and other cardiovascular disorders.

[0299] In still another aspect, the present compounds are effective indecreasing apoptosis in mammalian cells such as beta cells of Islets ofLangerhans.

[0300] In still another aspect, the present compounds are useful for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

[0301] In still another aspect, the present compounds may also be usefulfor improving cognitive functions in dementia, treating diabeticcomplications, psoriasis, polycystic ovarian syndrome (PCOS) andprevention and treatment of bone loss, e.g. osteoporosis.

[0302] In yet another aspect, the invention also relates to the use ofthe present compounds, which after administration lower the bio-markersof atherosclerosis like, but not limited to, c-reactive protein (CRP),TNFα and IL-6.

[0303] The present compounds may also be administered in combinationwith one or more further pharmacologically active substances eg.,selected from antiobesity agents, antidiabetics, antihypertensiveagents, agents for the treatment and/or prevention of complicationsresulting from or associated with diabetes and agents for the treatmentand/or prevention of complications and disorders resulting from orassociated with obesity.

[0304] Thus, in a further aspect of the invention the present compoundsmay be administered in combination with one or more antiobesity agentsor appetite regulating agents.

[0305] Such agents may be selected from the group consisting of CART(cocaine amphetamine regulated transcript) agonists, NPY (neuropeptideY) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators or TR β agonists.

[0306] In one embodiment of the invention the antiobesity agent isleptin.

[0307] In another embodiment the antiobesity agent is dexamphetamine oramphetamine.

[0308] In another embodiment the antiobesity agent is fenfluramine ordexfenfluramine.

[0309] In still another embodiment the antiobesity agent is sibutramine.

[0310] In a further embodiment the antiobesity agent is orlistat.

[0311] In another embodiment the antiobesity agent is mazindol orphentermine.

[0312] Suitable antidiabetics comprise insulin, GLP-1 (glucagon likepeptide-1) derivatives such as those disclosed in WO 98/08871 to NovoNordisk A/S, which is incorporated herein by reference as well as orallyactive hypoglycaemic agents.

[0313] The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as HMG CoAinhibitors (statins), compounds lowering food intake, RXR agonists andagents acting on the ATP-dependent potassium channel of the β-cells.

[0314] In one embodiment of the invention the present compounds areadministered in combination with insulin.

[0315] In a further embodiment the present compounds are administered incombination with a sulphonylurea eg. tolbutamide, glibenclamide,glipizide or glicazide.

[0316] In another embodiment the present compounds are administered incombination with a biguanide eg. metformin.

[0317] In yet another embodiment the present compounds are administeredin combination with a meglitinide eg. repaglinide or senaglinide.

[0318] In a further embodiment the present compounds are administered incombination with an α-glucosidase inhibitor eg. miglitol or acarbose.

[0319] In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the β-cells eg. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

[0320] Furthermore, the present compounds may be administered incombination with nateglinide.

[0321] In still another embodiment the present compounds areadministered in combination with an antihyperlipidemic agent orantilipidemic agent eg. cholestyramine, colestipol, clofibrate,gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156,LY-518674, LY-519818, MK-767, atorvastatin, fluvastatin, lovastatin,pravastatin, simvastatin, cerivastin, acipimox, ezetimibe, probucol,dextrothyroxine or nicotinic acid.

[0322] In yet another embodiment the present compounds are administeredin combination with a thiazolidinedione e.g. troglitazone, ciglitazone,pioglitazone or rosiglitazone.

[0323] In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds eg. incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and metformin, insulin and a sulphonylurea,insulin and metformin, insulin, insulin and lovastatin, etc.

[0324] Furthermore, the present compounds may be administered incombination with one or more antihypertensive agents. Examples ofantihypertensive agents are β-blockers such as alprenolol, atenolol,timolol, pindolol, propranolol and metoprolol, ACE (angiotensinconverting enzyme) inhibitors such as benazepril, captopril, enalapril,fosinopril, lisinopril, quinapril and ramipril, calcium channel blockerssuch as nifedipine, felodipine, nicardipine, isradipine, nimodipine,diltiazem and verapamil, and α-blockers such as doxazosin, urapidil,prazosin and terazosin. Further reference can be made to Remington: TheScience and Practice of Pharmacy, 19^(th) Edition, Gennaro, Ed., MackPublishing Co., Easton, Pa., 1995.

[0325] It should be understood that any suitable combination of thecompounds according to the invention with one or more of theabove-mentioned compounds and optionally one or more furtherpharmacologically active substances are considered to be within thescope of the present invention.

[0326] The present invention also relates to a process for thepreparation of the above said novel compounds, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts or pharmaceutically acceptablesolvates.

[0327] Pharmaceutical Compositions

[0328] The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995. Thecompositions may appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

[0329] Typical compositions include a compound of the present inventionor a pharmaceutically acceptable acid addition salt thereof, associatedwith a pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

[0330] The pharmaceutical compositions can be sterilized and mixed, ifdesired, with auxiliary agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like,which do not deleteriously react with the active compounds.

[0331] The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

[0332] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatin capsule in powderor pellet form or it can be in the form of a troche or lozenge. If aliquid carrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution.

[0333] For nasal administration, the preparation may contain a compoundof the invention dissolved or suspended in a liquid carrier, inparticular an aqueous carrier, for aerosol application. The carrier maycontain additives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

[0334] For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

[0335] Tablets, dragees, or capsules having talc and/or a carbohydratecarrier or binder or the like are particularly suitable for oralapplication. Preferable carriers for tablets, dragees, or capsulesinclude lactose, corn starch, and/or potato starch. A syrup or elixircan be used in cases where a sweetened vehicle can be employed.

[0336] A typical tablet which may be prepared by conventional tablettingtechniques may contain:

[0337] Core: Active compound (as free compound or salt thereof)   5 mgColloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst.(Avicel)  70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesiumstearate Ad.

[0338] Coating: HPMC approx.   9 mg *Mywacett 9-40 T approx. 0.9 mg

[0339] If desired, the pharmaceutical composition of the invention maycomprise the compound of the present invention in combination withfurther pharmacologically active substances such as those described inthe foregoing.

[0340] The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar.

[0341] Such mammals include also animals, both domestic animals, e.g.household pets, and non-domestic animals such as wildlife.

[0342] The compounds of the invention are effective over a wide dosagerange. A typical oral dosage is in the range of from about 0.001 toabout 100 mg/kg body weight per day, preferably from about 0.01 to about50 mg/kg body weight per day, and more preferred from about 0.05 toabout 10 mg/kg body weight per day administered in one or more dosagessuch as 1 to 3 dosages. The exact dosage will depend upon the frequencyand mode of administration, the sex, age, weight and general conditionof the subject treated, the nature and severity of the condition treatedand any concomitant diseases to be treated and other factors evident tothose skilled in the art.

[0343] The formulations may conveniently be presented in unit dosageform by methods known to those skilled in the art. A typical unit dosageform for oral administration one or more times per day such as 1 to 3times per day may contain of from 0.05 to about 1000 mg, preferably fromabout 0.1 to about 500 mg, and more preferred from about 0.5 mg to about200 mg.

[0344] Any novel feature or combination of features described herein isconsidered essential to this invention.

[0345] The present invention is further illustrated in the followingrepresentative examples which are, however, not intended to limit thescope of the invention in any way.

EXAMPLES

[0346] The following examples and general procedures refer tointermediate compounds and final products identified in thespecification and in the synthesis schemes. The preparation of thecompounds of the present invention is described in detail using thefollowing examples. Occasionally, the reaction may not be applicable asdescribed to each compound included within the disclosed scope of theinvention. The compounds for which this occurs will be readilyrecognised by those skilled in the art. In these cases the reactions canbe successfully performed by conventional modifications known to thoseskilled in the art, that is, by appropriate protection of interferinggroups, by changing to other conventional reagents, or by routinemodification of reaction conditions. Alternatively, other reactionsdisclosed herein or otherwise conventional will be applicable to thepreparation of the corresponding compounds of the invention. In allpreparative methods, all starting materials are known or may easily beprepared from known starting materials. The structures of the compoundsare confirmed nuclear magnetic resonance (NMR). NMR shifts (δ) are givenin parts per million (ppm). Mp is melting point and is given in ° C.

[0347] The abbreviations as used in the examples have the followingmeaning:

[0348] THF: tetrahydrofuran

[0349] DMSO: dimethylsulfoxide

[0350] CDCl₃: deutorated chloroform

[0351] DMF: N,N-dimethylformamide

[0352] min: minutes

[0353] h: hours

[0354] General Procedure (A)

[0355] Step A:

[0356] Reacting a compound of formula (a)

Hlg-Z-Hlg   (a)

[0357] wherein Z is defined as above and wherein Hlg is bromine oriodine, with an appropriate compound P, where P is an unsaturatedalkohol or an unsaturated ester, through a cross-coupling reactionemploying a Pd catalyst such as Pd(PPh₃)₂ or PdCl₂(PPh₃)₂ and acatalytic amount of in example copper(I)iodide and an organic aminebase, such as and if needed a co-solvent to give a compound of formula(b)

P-Z-Hlg   (b)

[0358] wherein Z and P are defined as above and wherein Hlg is bromineor iodine.

[0359] Step B:

[0360] Reacting a compound of formula (b) wherein Z and P are defined asabove and wherein Hlg is bromine or iodine, with a appropriate compoundof formula P′, wherein P′ is an unsaturated alkohol or an unsaturatedester, through a cross-coupling reaction employing a Pd catalyst such asPd(PPh₃)₂ or PdCl₂(PPh₃)₂ and a catalytic amount of in examplecopper(I)iodide and an organic amine base, such as and if needed aco-solvent to give a compound of formula (c)

P-Z-P′  (c)

[0361] wherein Z, P and P′ are defined as above.

[0362] Step C:

[0363] Reacting a compound of formula (c), wherein P, Z and P′ are asdefined above, with a reducing agent such as NaBH₄ or LiBH₄ to give acompounds of formula (d)

HO-T-Z-U—OH   (d)

[0364] wherein T, Z and U are defined as above.

[0365] Step D:

[0366] Reacting a compound of formula (d), wherein T, Z and U aredefined as above, with a compound of formula (e)

[0367] wherein A, X and D are defined as above except that D is nothydrogen, under Mitsunobu conditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like, to obtain acompound of formula (f)

[0368] wherein A, D, L, T, U, X, and Z are defined as above, except thatD is not hydrogen.

[0369] Step E:

[0370] Reacting a compound of formula (f), wherein A, D, L, T, U, X, andZ are defined as above, except that D is not hydrogen, with a compoundof formula (g)

[0371] wherein B, M, Y and E are defined as above except that E is nothydrogen, under Mitsunobu conditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like, to obtain acompound of formula (I), wherein A, B, D, E, L, M, T, U, X, Y and Z aredefined as above, except that D and E are not hydrogen.

[0372] Step D and E may be carried out in one step giving a compound offormula (I), wherein A and B are identical, D and E are identical, L andM are identical and X and Y are identical.

[0373] General Procedure (B)

[0374] Step A:

[0375] Converting the —OH functionality in the compound of formula (d),wherein T, Z and U are defined as above, to an appropriate leaving group(Q) such as p-toluenesulfonate, methanesulfonate, halogen (for exampleby methods according to: Houben-Weyl, Methoden der organischen Chemie,Alkohole III, 6/1b, Thieme-Verlag 1984, 4th Ed., pp. 927-939;Comprehensive Organic Transformations. A guide to functional grouppreparations, VCH Publishers 1989, 1^(st) Ed., pp. 353-363 and J. Org.Chem., Vol. 36 (20), 3044-3045, 1971), triflate and the like, to give acompound of formula (h)

Q-T-Z-U-Q   (h)

[0376] wherein Q, T, U and Z are defined as above.

[0377] Step B:

[0378] Reacting the compound of formula (h) wherein Q is a leaving groupsuch as p-toluenesulfonate, methanesulfonate, halogen, triflate and thelike and wherein T, U and Z are defined as above with a compound offormula (e), wherein A, L, X and D are defined as above except that D isnot hydrogen, to give a compound of formula (i)

[0379] wherein A, D, L, Q, T, U, X, and Z are defined as above, exceptthat D is not hydrogen.

[0380] Step C:

[0381] Reacting the compound of formula (i) wherein Q is a leaving groupsuch as p-toluenesulfonate, methanesulfonate, halogen, triflate and thelike and wherein A, D, L, Q, T, U, X, and Z are defined as above with acompound of formula (g), wherein B, M, Y and E are defined as aboveexcept that E is not hydrogen, to give a compound of formula (I) whereinA, B, D, E, L, M, T, U, X, Y and Z are defined as above, except that Dand E is not hydrogen.

[0382] Step B and C may be carried out in one step giving a compound offormula (I), wherein A and B are identical, D and E are identical, L andM are identical and X and Y are identical.

[0383] General Procedure (C)

[0384] Step A:

[0385] By chemical or enzymatic saponification of a compound of formula(I) wherein A, B, D, E, L, M, T, U, X, Y and Z are defined as above,except that D and E are not hydrogen, to give a compound of formula (I)wherein A, B, L, M, T, U, X, Y and Z are defined as above, and wherein Dand E is hydrogen.

[0386] General Procedure (D)

[0387] Step A:

[0388] Hydrolyze a compound of formula (I), wherein A, B, D, E, L, M, T,U, X, Y and Z are defined as above, except that D and E are nothydrogen, to give a compound of formula (I) wherein A, B, L, M, T, U, X,Y and Z are defined as above, and wherein D and E is hydrogen, usingaqueous NaOH or the like.

[0389] General Procedure (E)

[0390] Step A:

[0391] Reacting a compound of formula (a), wherein Z is defined as aboveand wherein Hlg is bromine or iodine, with a compound of formulaHO-T′-HNR₁, wherein T′ and R₁ are as defined, above, to give a compoundof formula (j)

HO-T′-NR₁.Z-Hlg   (j)

[0392] wherein T′, R₁ and Z is defined as above and wherein Hlg isbromine or iodine.

[0393] Step B:

[0394] Reacting a compound of formula (J), wherein T′, R₁ and Z isdefined as above and wherein Hlg is bromine or iodine, with a compoundof formula HO—U′—HNR₁, wherein U′ and R₁ are as defined above, to give acompound of formula (k)

HO-T′-NR₁.Z-NR₁U′—OH   (k)

[0395] wherein T′, R₁, U′, Z are as defined above.

[0396] Step C:

[0397] Reacting a compound of formula (k), wherein T′, Z and U′ aredefined as above, with a compound of formula (e), wherein A, X and D aredefined as above except that D is not hydrogen, under Mitsunobuconditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like, to obtain acompound of formula (m)

[0398] wherein A, D, L, R₁, T′, U′, X, and Z are defined as above,except that D is not hydrogen.

[0399] Step D:

[0400] Reaction a compound of formula (m), wherein A, D, L, T′, R₁, U′,X, and Z are defined as above, except that D is not hydrogen, with acompound of formula (g), wherein B, M, Y and E are defined as aboveexcept that E is not hydrogen, under Mitsunobu conditions, using areagent such as triphenylphosphine/diethylazodicarboxylate and the like,to obtain a compound of formula (n),

[0401] wherein A, B, D, E, L, M, T, R₁, U′, X, Y and Z are defined asabove, except that D and E are not hydrogen.

[0402] Step D and E may be carried out in one step giving a compound offormula (n), wherein A and B are identical, D and E are identical, L andM are identical and X and Y are identical.

[0403] Intermediate 1

(4-Mercapto-2-methyl-phenoxy)-acetic acid methyl ester

[0404]

[0405] Step 1:

[0406] o-Cresol (100 g, 0.925 mol) was dissolved in 2-butanone (1200ml), potassium carbonate (191.7 g, 1.5 mol) and ethyl bromoacetate(162.2 g, 0.971 mol) were added and the mixture was refluxed understirring for 24 h and then left to stand overnight. The solid wasfiltered off, the filtrate was evaporated and dissolved in benzene (400ml). The solution was washed with water (200 ml), 5% solution of sodiumcarbonate (100 ml) and dried over MgSO₄. The residue (ca 200 g) wasdistilled in vacuo. This afforded 161.9 g (90.1 %) of(2-methyl-phenoxy)-acetic acid ethyl ester, b.p. 120-130° C./2 kPa.

[0407] Step 2:

[0408] Chlorosulfonic acid (180.9 g, 104 ml, 1.553 mol) was cooled to−2-0° C. and then the above (2-methyl-phenoxy)-acetic acid ethyl ester(75.35 g, 0.388 mol) was added drop-wise under stirring at such ratethat the temperature of the reaction mixture did not exceed 0° C. (20min). The mixture was left to warm to ambient temperature (1 h) and thenpoured on crushed ice (1 kg). The crystalline product was filtered off,washed with water (500 ml) and dried on air to constant weight. Thisgave 108.4 g (95.5%) crude (4-chlorosulfonyl-2-methylphenoxy)-aceticacid ethyl ester. The product was crystallized from cyclohexane (500 ml)affording 73.3 g (64.6%) pure product. M.p. 86-89° C.

[0409]¹H NMR (300 MHz, CDCl₃): δ 7.84 (m, 2 H); 6.80 (m, 1 H); 4.76 (s,2 H); 4.29 (q, J=7.1 Hz); 2.37 (s, 3 H); 1.31 (s, 3 H).

[0410] Step 3:

[0411] To the mixture of above sulfochloride (97.7 g, 0.333 mol), tin(189.9 g, 1.59 mol) and methanol (170 ml) concentrated hydrochloric acidwas added dropwise under vigorous stirring during 20 min. The reactionbecame exothermic and began to reflux spontaneously.

[0412] The reaction mixture was further heated to reflux for 3 hours,then cooled and poured to crushed ice (1 kg). The mixture was extractedwith diethyl ether (3×200 ml), the ethereal solutions were washed withwater (2×80 ml), dried over MgSO₄ and evaporated in vacuo. The residue(97.7 g) was dissolved in benzene (300 ml), passed trough column ofsilica gel (Fluka 60, 800 g) and the column was washed with benzene(2500 ml). Collected benzene solutions were evaporated and the residuewas distilled in vacuo. This afforded 41.3 g (58.4%) of(4-mercapto-2-methylphenoxy)-acetic acid methyl ester as oil, b.p.136.5-137° C./133 Pa.

[0413]¹H NMR (250 MHz, CDCl₃): δ 7.04 (m)+7.04 (m), Σ 2 H; 6.54 (m, 1H); 2.20 (m, 3 H); 4.56 (s, 2 H); 3.73 (s, 3 H); 3.34 (s, 1 H).

[0414] Intermediate 2

2-Ethoxy-3-(4-mercapto-phenyl)-propionic acid methyl ester

[0415]

[0416] Method A:

[0417] Step 1:

[0418] A mixture of ethyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (100.8g, 0.423 mol), triethylamine (83.4 g, 115 ml, 0.824 mol),4-dimethylaminopyridine (5.2 g, 42.3 mmol) and dimethylthiocarbamoylchloride (62.6 g, 0.507 mol) in dioxane (640 ml) was stirred and heatedat 100° C. for 10 h in nitrogen atmosphere. The solid was filtered off,washed with dioxane and the filtrates were evaporated in vacuo. Theresidue was dissolved in dichloromethane (600 ml), the solution waswashed with water (3×250 ml), dried (MgSO₄) and passed through column ofsilica gel (Fluka 60, 500 g). The column was washed with 500 mldichloromethane, collected dichloromethane solutions were evaporated toyield 140.1 g (˜100%) of3-(4-dimethylthiocarbamoyloxy-phenyl)-2-ethoxy-propionic acid ethylester as an oil, which was used to next step.

[0419] Step 2:

[0420] The mixture the above compound (140 g, 0.423 mol) and tetradecane(1000 ml) was vigorously stirred under argon atmosphere at 230-245° C.for 8 h. The reaction mixture was cooled, tetradecane layer wasseparated and the residue was decanted with n-hexane (2×150 ml). Theresidue was dissolved in benzene (150 ml) and passed through a column ofsilica gel (Fluka 60, 600 g). The column was washed with benzene (4000ml) and collected benzene solutions were evaporated in vacuo. Thisafforded 90.2 g (65.5%) of3-(4-dimethyl-carbamoylsulfanyl-phenyl)-2-ethoxypropionic acid ethylester as an oil.

[0421]¹H NMR (300 MHz, CDCl₃): δ 7.41 (d, J=4.5 Hz, 2 H); 7.26 (d, J=4.5Hz, 2 H); 4.15 (a, J=7.2 Hz, 2 H); 3.99 (t, J=5.8 Hz, 1 H); 3.59 (quint,1 H); 3.33 (quint, 1 H); 2.99 (m, 6 H); 1.23 (t, J=7.1 Hz, 3 H); 1.17(t, J=7.1 Hz, 3 H).

[0422] Step 3:

[0423] The solution of above ester (90.0 g, 0.2765) in tetrahydrofuran(370 ml) was cooled to 10° C. The solution of 85% potassium hydroxide(58.4 g, 0.885 mol) in methanol (150 ml) was added dropwise and thereaction mixture was stirred at ambient temperature for 15 h. Diethylether (250 ml) and water (250 ml) were added and the mixture wasacidified under cooling and stirring with 15% hydrochloric acid (pH=1).The ethereal layer was separated. and water the layer was extracted withdiethyl ether (3×250 ml). Collected organic solutions were washed withwater (2×100 ml), brine (80 ml), dried (MgSO₄) and evaporated in vacuo.The residue was purified by chromatography (silica gel Fluka 60, 600 g).Elution with chloroform (2000 ml) and then with mixture ofchloroform/methanol 95: 5 (1000 ml) yielded 64 g (˜100%) of2-ethoxy-3-(4-mercapto-phenyl)-propionic acid as an oil.

[0424]¹H NMR (300 MHz, CDCl₃): δ 7.17 (m, 2 H); 7.11 (m, 2 H); 4.01 (dd,1 H); 3.62 (dq, 1 H); 3.38 (dq, 1 H); 3.42 (s, 1 H); 2.98 (m, 2 H); 1.15(t, 3 H).

[0425] Step 4:

[0426] A stream of gaseous hydrogen chloride was introduced to thesolution of above acid (56.1 g, 0.248 mol) in methanol (450 ml) andbenzene (90 ml) at 30-35° C. for 6 h. The reaction mixture was left tostand overnight, diluted with benzene (400 ml) and poured to crushed ice(500 g). The benzene layer was separated and the water layer wasextracted with diethyl ether (2×200 m). Collected organic layers werewashed with water (4×150 ml), dried over MgSO₄, filtrated through silicagel (60 g) and evaporated. The residue vas distilled in vacuo to yield48.4 g (81.2%) of the title compound. B.p.130° C./200 Pa.

[0427]¹H NMR (250 MHz, CDCl₃): δ 7.18 (m, 2 H); 7.09 (m, 2 H); 3.43 (s,1 H); 2.94 (m, 2 H); 3.99 (dd, J=5.6 and 7.4 Hz, 1 H); 3.68 (s, 3 H);3.32 (dqua, J=7.0 and 9.10 Hz, 1 H); 3.59 (dqua, J=7.0 and 9.14 Hz, 1H); 1.14 (t, J=7.0 Hz, 3 H).

[0428] Method B:

[0429] Step 1:

[0430] A solution of ethyl 2-ethoxycinnamate (53.9 g, 0.267 mol;prepared as described in Justus Liebigs Ann. Chem. 699, 53 (1966) ) inethanol (500 ml) was hydrogenated in the presence of 5% palladium onactivated charcoal (5.0 g) at ambient temperature under pressure 10 atmuntil absorption of hydrogen ceased. The catalyst was filtered off andthe filtrate was evaporated to give 52.8 g (97%) of ethyl2-ethoxy-3-phenylpropionate as an oil.

[0431] Step 2:

[0432] Chlorosulfonic acid (110.8 g, 0.95 mol) was cooled to −2-0° C.and then the above ester (52.8 g, 0.238 mol) was added dropwise understirring at such rate that the temperature of the reaction mixture didnot exceed 0° C. (20 min). The mixture was stirred for 1 h, poured oncrushed ice (1 kg) and extracted with dichloromethane (300 ml). Theorganic layer was dried (MgSO₄) and evaporated. This gave 36.6 g (43.7%)of crude 3-(4-chlorosulfonyl-phenyl)-2-ethoxypropionic acid ethyl ester,which was used for the next step without purification.

[0433] Step 3:

[0434] To the mixture of above sulfochloride (36.6 g, 0.114 mol), tin(65.4 g, 0.55 gat) and methanol (60 ml) concentrated hydrochloric acidwas added dropwise under vigorous stirring during 20 min. The reactionbecame exothermic and began to reflux spontaneously.

[0435] The reaction mixture was further heated to reflux for 3 hours,then cooled and poured to crushed ice (1 kg). The mixture was extractedwith dichloromethane (2×200 ml), organic layer was washed with water(2×80 ml), dried over MgSO₄ and evaporated in vacuo. The residue wasdissolved in benzene (100 ml), passed trough column of silica gel (Fluka60, 300 g) and the column was washed with benzene (750 ml). Collectedbenzene solutions were evaporated and the residue was distilled invacuo. This afforded 14 g (51%) of the title compound as oil B.p.136.5-137° C./133 Pa.

[0436] Intermediate 3

Ethyl 2,6-diphenyl-4-hydroxyphenoxyacetate

[0437]

[0438] Step 1:

[0439] A mixture of 4-acetoxy-2,6-diphenylphenol (6.1 g, 20 mmol;prepared as described in Ber. 101, 2519 (1968) ), ethyl bromoacetate(4.0 g, 24 mmol), potassium carbonate (3.3 g, 24 mmol) and 2-butanone(150 ml) was refluxed for 24 h, then filtered and the solventevaporated. The residue was purified by chromatography on silica gel(120 g, eluent benzene) to give 7.2 g (92%) of oily ethyl4-acetoxy-2,6-diphenylphenoxyacetate .

[0440]¹H NMR (300 MHz, CDCl₃): δ 7.64 (m, 4 H); 7.37 (m, 6 H); 7.08 (s,2 H); 3.93 (q, J=7.1, 2 H); 3.79 (s, 2 H); 1.07 (t, J=7.1, 3 H).

[0441] Step 2:

[0442] The above ester (7.2 g, 18.5 mmol) was dissolved in wet toluene(400 ml) and a catalyst (25 g SiO₂ treated with a solution of 2 g4-toluenesulfonic acid in 10 ml acetone and evaporated in vacuo) wasadded. The mixture was stirred and heated at 100° C. for 6 h, cooled andfiltered through a column of silica gel (50 g). Elution with benzeneafforded 3.6 g (56%) of the title compound as white crystals, which wererecrystallized from benzene/petroleum ether. M.p. 91-93° C.

[0443]¹H NMR (250 MHz, CDCl₃): δ 1.05 (t, J=7.2 Hz, 3 H); 3.92 (q, J=7.2Hz, 2 H); 3.73 (s, 2 H); 6.82 (s, 2 H); 7.60 (m, 4 H); 7.35 (m, 6 H).

[0444] Intermediate 4 (General Procedure E)

2-({6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethanol

[0445]

[0446] Step A-B:

[0447] A mixture of 2,6-dibromopyridine (82.9 g, 0.35 mol) and2-(methylamino)ethanol (525.8 g, 7 mol) was stirred at 120-140° C. for20 h. Ethyl acetate (900 ml) and water (600 ml) were added understirring, organic layer was separated and water layer was extracted withethyl acetate (5×250 ml). Collected organic layers were washed withbrine (80 ml), dried over MgSO₄, evaporated to volume 500 ml and passedthrough a column of silica gel (Fluka 60, 600 g). The column was washedwith ethyl acetate (2.5 l), collected solutions were evaporated anddried in vacuo. This afforded 68.6 g (86.2%) of the title compound as anoil.

[0448]¹H NMR (250 MHz, CDCl₃): δ 7.26 (t, J=8.0 Hz, 1 H); 5.79 (d, J=8.1Hz, 2 H); 4.49 (bs, 2 H); 3.74 (m, 4 H); 3.61 (m, 4 H); 2.97 (s, 6 H).

[0449] Intermediate 5 (General Procedure A)

3-[4′-(3-Hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol

[0450]

[0451] Step 1:

[0452] 2,2′-Bistrifluoromethyl-4,4′-diaminobiphenyl (42,6 g, 133 mmol;prepared as described in J.Chem.Soc 1951, 3459) was dissolved in aceticacid (300 ml) and concentrated sulphuric acid (50 ml) was added. Theresulted suspension was diazotized with NaNO₂ (20.2 g, 293 mmol) in 50ml water at 5° C. for 1 h, then filtered and poured into a solution ofKl (220 g, 1.35 mol) in 800 ml water. The mixture was stirred for 3 h,extracted with benzene (300 ml), washed with 5% NaHSO₃, dried (MgSO₄)and benzene was evaporated in vacuo. The residue was purified bychromatography on silica gel to give 56.5 g (78.4%) of2,2′-bistrifluoromethyl-4,4′-diiodobiphenyl. M.p. 119-120° C.

[0453] Step A-B:

[0454] A mixture of the above diiododerivative (56.5 g, 104.3 mmol),palladium(II)acetate (0.7 g, 3.1 mmol), triphenylphosphine (2.1 g, 8mmol), triethylamine (20 g, 198 mmol) and methyl acrylate (28 g, 325mmol) in 120 ml dimethylformamide was heated at 110° C. for 5 h. Thereaction mixture was poured in water, extracted with benzene, dried(MgSO₄) and evaporated in vacuo. The residue was submitted tochromatography on silica gel (benzene/chloroform). First fractionafforded 10.7 g (27.4%) of methyl3-(2,2′-bistrifluoromethylbiphenyl-4-yl)acrylate, M.p. 97-98° C.(cyclohexane).

[0455] Next fraction yielded 18.3 g (38.3%) of2,2′-bistrifluoromethylbiphenyl-4,4′-diacrylic acid dimethyl ester.M.p.158-161° C. (cyclohexane).

[0456] Step C:

[0457] 2,2′-Bistrifluoromethylbiphenyl-4,4′-diacrylic acid dimethylester (11.5 g, 25.1 mmol) was dissolved in 200 ml polyethylene glycol(PEG 400) and sodium borohydride (6.5 g, 172 mmol) was added graduallyduring 30 min at 130° C. The mixture was heated at this temperature for6 h. After cooling water was added, the mixture was extracted withchloroform, dried (MgSO₄) and evaporated to give a residue which wassubmitted to chromatography on silica gel. Elution with ethyl acetateafforded 3.57 g (35%) of the title compound as an oil.

[0458]¹H NMR (250 MHz, CDCl₃): δ 7.55 (d, J=1.4 Hz, 2 H); 7.35 (dd,J=1.4 and 7.7 Hz, 2 H); 7.18 (d, J=7.7 Hz, 2 H); 3.72 (t, J=6.3 Hz, 4H); 2.83 (t, J=7.8 Hz, 4 H); 1.96 (m, 4 H); 1.65 (bs, 2 H).

[0459] Intermediate 6 (General Procedure A)

3-[4′-(3-Hydroxy-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol

[0460]

[0461] Step C:

[0462] 3,3′-Bistrifluoromethylbiphenyl-4,4′-diacrylic acid dimethylester (12.3 9, 26.8 mmol; prepared the same manner as 2,2′-isomer,intermediate 5, step A-B) was dissolved in 200 ml polyethylene glycol(PEG 400) and sodium borohydride (7.4 g, 196 mmol) was added graduallyduring 30 min at 130° C. The mixture was heated at this temperature for6 h, after cooling water was added and the mixture was extracted withchloroform. Chloroform extract was dried (MgSO₄) and evaporated to givea residue which was submitted to chromatography on silica gel. Elutionwith ethyl acetate afforded 1.85 g of the title compound as whitecrystals.

[0463] M.p. 87.5-90° C. (cyclohexane).

[0464]¹H NMR (300 MHz, CDCl₃): δ 7.78 (s, 2 H); 7.63 (d, J=8.2 Hz, 2 H);7.42 (d,J=8.2 H); 3.75 (t, J=6.4 Hz, 4 H); 2.92 (t, J=7.9 Hz, 4 H); 2.17(bs, 2 H); 1.93 (m, 4 H).

[0465] Intermediate 7

(S)-3-(3-Bromo-4-hydroxy-phenyl)-2-ethoxy-propionic acid isopropyl ester

[0466]

[0467] To a solution of (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acidisopropyl ester (7.56 g, 30 mmol) in methylene chloride (75 ml) wasadded drop wise under nitrogen a solution of Br₂ in methylene chloride(30 ml) at room temperature. The reaction was stirred for 60 min afterwhich a saturated aqueous solution of Na₂SO₃ (50 ml) was added.Methylene chloride (100 ml) was added and the methylene phase wasisolated. The organic phase was washed with brine (50 ml), dried andevaporated. The residue was purified by column chromatography usingheptane: ethyl acetate (3:1) as eluent. The title compound was isolatedin 8.91 g (90%) yield.

[0468]¹H NMR (300 MHz, CDCl₃): 6 7.37 (s, 1H); 7.10 (d, J=8 Hz, 1H);6.93 (d, J=8 Hz, 1H); 5.05 (m, 1H); 3.93 (t, J=6Hz, 1H); 3.63 (m, 1H);3.35 (m, 1H); 2.92 (d, J=6 Hz, 2H); 1.30-1.114 (m, 9H).

[0469] Intermediate 8 (General Procedure A)

3-[7-(3-Hydroxy-propyl)-9H-fluoren-2-yl]-propan-1-ol

[0470]

[0471] Step A-B:

[0472] A mixture of 2,7-dibromofluorene (48.6 g, 0.15 mol, Ber. 53, 1236(1920) ), palladium(II)acetate (1.0 g, 4.45 mmol), triphenylphosphine(3.0 g, 11.4 mmol), triethylamine (30.3 g, 0.3 mol), methyl acrylate(38.7 9, 0.45 mol) and dimethylformamide (150 ml) was stirred and heatedat 110° C. for 7 h. The mixture was poured into water (1000 ml), theresulted solid was filtered off and recrystallized from chloroform togive 36.8 g (73.9%) of fluorene-2,7-diacrylic acid dimethyl ester. M.p.206-209° C.

[0473]¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (m, 4 H); 7.75 (m, 2 H); 7.73 (d,J=15.9 Hz, 2 H); 6.69 (d, J=15.9 Hz, 2 H); 3.98 (s, 2 H); 3.73 (s, 6 H).

[0474] Step C:

[0475] A mixture of sodium borohydride (3.7 g, 98 mmol) and lithiumchloride (4.2 g, 101 mmol) in ethanol (70 ml) was stirred at 5° C. for15 min, 9H-fluorene-2,7-diacrylic acid dimethyl ester (5.0 g, 15 mmol)in diglyme (150 ml) was added portionwise at 20-50° C. and the mixturewas refluxed for 18 h. Diluted hydrochloric acid was added dropwiseafter cooling and the mixture was extracted with diethyl ether. Organiclayer was separated, dried (MgSO₄) and evaporated to give a residue,which was purified by chromatography on silica gel. Elution with ethylacetate afforded 1.85 g (44%) of the title compound as white crystals.

[0476] M.p. 160-180° C.

[0477]¹H NMR (300 MHz, CDCl₃): δ 7.65 (d, J=7.0 Hz, 2 H); 7.35 (s, 2 H);7.18 d, J=7.7 Hz, 2 H); 3.84 (s, 2 H); 3.71 (t, J=6.3 Hz, 4 H); 2.78 (t,J=7.6 Hz, 4 H); 1.95 (m, 4 H); 1.59 (bs, 2 H).

[0478] Intermediate 9

2-(2-{3-[4-(2-Hydroxy-ethyl)-5-methyl-oxazol-2-yl]-phenyl}-5-methyl-oxazol-4-yl)-ethanol

[0479]

[0480] Step 1:

[0481] A solution of sodium carbonate (62.8 g, 0.592 mol) in water (1500 ml) was added to the suspension of 4-benzyl L-aspartate (89.6 g, 0.4mol) in dioxane (600 ml) and the mixture was stirred until a clearsolution was obtained (30 min). A solution of terephtaloyl chloride(40.4 g, 0.199 mol) in dioxane (400 ml) was added dropwise at ambienttemperature during 2 h, the reaction mixture was stirred at ambienttemperature for the next 3 h and then left to stand overnight. Thesolution was washed with diethyl ether (2×500 ml), acidified with 10%hydrochloric acid to pH=2 and the product was extracted withdichloromethane (3×500 ml). Collected filtrates were washed with water(200 ml), brine (100 ml), dried with MgSO₄ and evaporated in vacuo toyield 128.8 g (56.7%) of2-[3-(2-benzyloxycarbonyl-1-carboxy-ethylcarbamoyl)-benzoylamino]-succinicacid 4-benzyl ester as a white solid.

[0482]¹H NMR (250 MHz, DMSO-d₆): δ 9.03 (d, J=8.0 Hz, 2 H); 8.37 (m, 1H); 8.00 (dd, J=1.6 and 7.8 Hz, 2 H); 7.63 (m); 5.14 (s, 4 H); 4.89 (m,2 H); 3.05 (dd, J=5.7 and 16.2 Hz, 2 H); 2.9 (dd, J=8.4 and 16.2 Hz, 2H).

[0483] Step 2:

[0484] Acetanhydride (600 ml) was added dropwise to the solution ofabove diester (110.5 g, 0.191 mol) in pyridine (600 ml) during 1.5 h andthe reaction mixture was stirred at 95° C. for 2 h. The dark solutionwas cooled to 80° C., water (325 ml) was added dropwise at such a ratethat the mixture refluxed vigorously (30 min), warmed to reflux for thenext 30 min and left to stand overnight. The reaction mixture wasacidified with 10% hydrochloric acid (1800 ml), extracted with ethylacetate (1000 ml, 2×500 ml), collected extracts were washed with water(200 ml), dried MgSO₄ and evaporated in vacuo to yield 97.1 g (88.8%) ofcrude3-[3-(1-benzyloxycarbonylmethyl-2-oxo-propylcarbamoyl)-benzoylamino]-4-oxo-pentanoicacid benzyl ester as an oil which was used directly to next step.

[0485] Step 3:

[0486] The above compound (95.0 g, 0.166 mol) was dissolved in toluene(1000 ml) phosphorus oxychloride (320 ml) was added and the mixture wasstirred at reflux temperature for 4 h. After standing overnight themixture was poured on ice (3 kg) and neutralized with solid potassiumcarbonate (1.6 kg) under stirring. The mixture was extracted withdiethyl ether (3×600 ml), the extracts were washed with brine (2×200ml), dried (MgSO₄) and evaporated in vacuo. The residue (106 g) waschromatographed on the column of SiO₂ (Fluka 60, 1000 g).

[0487] Elution with benzene gave by-products (10.5 g), elution withbenzene/ethyl acetate (9:1) afforded 22.8 g (25.6%) of{2-[3-(4-benzyloxycarbonylmethyl-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-aceticacid benzyl ester, m.p. 98-100° C.

[0488] Step 4:

[0489] A solution of the above diester (21.4 g, 39.8 mmol) intetrahydrofuran (800 ml) was added dropwise to a suspension of lithiumaluminum hydride (3.0 g, 79.7 mmol) in diethyl ether (200 ml) at 0° C.during 60 min. The mixture was stirred 30 min at the same temperature, 4h at ambient temperature and then left to stand overnight. The reactionmixture was decomposed by successive addling water (3 ml), 15% solutionof sodium hydroxide (3 ml) and water (10 ml). The suspension was stirredat ambient temperature for 3 h, the solid was filtered off, washed withtetrahydrofuran (100 ml) and ethyl acetate (300 ml). The collectedfiltrates were dried (MgSO₄) and evaporated. The residue (23 g) wassubmitted to chromatography (silica gel Fluka 60, 500 g). Elution withethyl acetate and ethanol (95:5) gave the title product (10.1 g, 77.2%),m.p. 134-135° C.

[0490]¹H NMR (250 MHz, DMSO-d₆): δ 8.41 (s, 1 H); 7.98 (d, J=7.8 Hz, 2H); 7.67 (t, J=7.7 Hz, 1 H); 4.68 (t, J=5.4 Hz, 2 H); 3.67 (q, J=6.6 Hz,4 H); 2.64 (t, J=6.7 Hz, 4 H); 2.38 )s, 6 H).

[0491] Intermediate 10

2-(2-{4′-[4-(2-Hydroxy-ethyl)-5-methyl-oxazol-2-yl]-biphenyl-4-yl}-5-methyl-oxazol-4-yl)-ethanol

[0492]

[0493] Step 1:

[0494] L-Aspartic acid 4-benzylester (78.1 g, 0.35 mol) was suspended indioxane (1000 ml), the solution of sodium carbonate (56 g, 0.52 mol) inwater (1200 ml) and the mixture was stirred for 1 h.Biphenyl-4,4′-dicarbonyl dichloride (48.9 g, 0.175 mol) was addedportion-wise to this mixture during 2 h and the reaction mixture wasstirred at ambient temperature for 3 h. Water was added (350 ml), andthe mixture was left to stand overnight and then washed with diethylether (3×350 ml). The water layer was acidified with 10% hydrochloricacid, the precipitated solid was filtered, washed with water and dried.Yield of crude2-{[4′-(2-benzyloxycarbonyl-1-carboxy-ethylcarbamoyl)-biphenyl-4-carbonyl]-amino}-succinicacid 4-benzyl ester was 69.5 g (60.8%). M.p. 204-207° C.

[0495]¹H NMR (250 MHz, DMSO-d₆): δ 8.97 (d, 2 H); 7.99 (m, 4 H); 7.90(m, 4 H); 7.36 (m, 10 H); 5.15 (s, 4 H); 4.90 (m, 2 H); 3.20 (bs); 2.99(m, Σ 4 H).

[0496] Step 2:

[0497] The above compound (68.9 g, 0.145 mol) was dissolved in absolutepyridine (300 ml) and then acetic anhydride (300 ml) was addeddrop-wise. The reaction mixture was warmed up to 95° C., stirred for 3.5h, and cooled to 80° C. Water (160 ml) was added (temperature between100-120° C.) and then the reaction mixture was stirred at 90° C. for 1 hand left to stand overnight. Hydrochloric acid (10%, 900 ml) was addedunder ice cooling, and the precipitated solid was filtered off andwashed with water (3×250 ml). This afforded, after drying on air, 58.5 g(85.5%) crude3-{[4′-(1-benzyloxycarbonylmethyl-2-oxo-propylcarbamoyl)-biphenyl-4-carbonyl]-amino}-4-oxo-pentanoicacid benzyl ester. M.p.165-168° C.

[0498]¹H NMR (250 MHz, DMSO-d₆): δ 9.25 (d, 2 H); 8.03 (m, 4 H); 7.91(m, 4 H); 7.35 (m, 10 H); 5.14 (s, 4 H); 4.82 (m, 2 H); 3.12 and 3.78(m, Σ 4 H); 2.20 (s, 6 H).

[0499] Step 3:

[0500] The mixture of above compound (57.4 g, 0.123 mol), toluene (600ml) and phosphorus oxychloride (160 ml) was stirred at refluxtemperature for 4 h. The mixture was cooled to 50° C., poured on ice(1500 g) and neutralized with solid potassium carbonate (600 g) understirring. The mixture was extracted with diethyl ether (3×500 ml) andchloroform (3×200), the extracts were combined, powdery polymers werefiltered off and the filtrate was washed with water (100 ml), brine (80ml), dried (MgSO₄) and evaporated in vacuo. The residue (41 g) waschromatographed on the column of SiO₂ (Fluka 60, 800 g). Elution withbenzene/ethyl acetate (9: 1) afforded 6.2 g (12.5%) of{2-[4′-(4-benzyloxycarbonylmethyl-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-aceticacid benzyl ester, m.p.162-168° C.

[0501]¹H NMR (300 MHz, DMSO-d₆): δ 7.98 (m, 4 H); 7.88 (m, 4 H); 7.35(m, 10 H); 5.14 (s, 4 H); 3.71 (s, 4 H); 2.36 (s, 6 H).

[0502] Step 4:

[0503] The solution of above diester (6.0 g, 14.8 mmol) intetrahydrofuran (500 ml) was added drop-wise to a suspension of lithiumaluminum hydride (1.12 g, 29.7 mmol) in diethyl ether (150 ml) at 5° C.during 60 min. The mixture was stirred the next 2 h at the sametemperature, and 2 h at ambient temperature. The reaction mixture wasdecomposed by successive addling water (1.1 ml), 15% solution of sodiumhydroxide (1.1 ml) and water (3.5 ml). The suspension was stirred atambient temperature for 1.5 h, the solid was filtered off, and washedwith tetrahydrofuran (50 ml) and chloroform (100 ml). The collectedfiltrates were dried (MgSO₄) and evaporated. The residue (2.9 g) wassubmitted to chromatography (silica gel Fluka 60, 200 g). Elution withethyl acetate and ethanol (95:5 and then 40:60) gave the title compound(0.95 g, 15.8%), m.p. 134-135° C.

[0504]¹H NMR (250 MHz, DMSO-d₆): δ 8.01 (m, 4 H); 7.87 (m, 4 H); 4.70(bt, 2 H); 3.69 (m, 4 H); 2.65 (t, J=7.7 Hz, 4 H); 2.36 (s, 6 H).

[0505] Intermediate 11

(4-Mercapto-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester

[0506]

[0507] Step 1:

[0508] A mixture of 2-trifluoromethyl-4-nitrophenol (73.4 g, 0.354 mol),ethyl bromoacetate (65.2 g, 0.39 mol), potassium carbonate (58.7 g,0.425 mol) and 2-butanone (400 mL) was refluxed under stirring for 10 h.The solid was filtered off, the filtrate was evaporated and the residuewas fractionated yielding 97.8 g (95%) of2-trifluromethyl-4-nitrophenoxyacetic acid ethyl ester, b.p. 126° C./40Pa.

[0509] Step 2:

[0510] The above ester (97.8 g, 0.334 mol) was dissolved in ethanol (450mL), 5%Pd/C (6.0 g) was added and the mixture was hydrogenated at normalpressure and temperature for 3 h. The catalyst was removed byfiltration, ethanol was evaporated and the residual4-amino-2-trifluoromethyl-phenoxyacetic acid ethyl ester (87.6 g, 0.334mol) was added to the mixture of conc. hydrochloric acid (65 mL) andwater (170 mL). The mixture was cooled to 5° C. and then a solution ofsodium nitrite (23.0 g, 0.334 mol) in water (90 mL) was added dropwisetogether with cracked ice to keep the temperature below 5° C. This takesabout 5 min. In another beaker, 100 mL water was warmed to reflux andthen Na₂S.3H₂O (46.5 g, 0.367 mol) and powdered sulfur (11.7 g, 0.367mol) were dissolved by heating and stirring. A solution of sodiumhydroxide (13.3 g, 0.334) mol in water (30 mL) was then added and themixture was cooled below 5° C. The solution of diazonium salt was addedalong with ice to prevent the temperature rising. When addition wascomplete, the mixture was allowed to warm up to laboratory temperatureovernight and filtered. The filtrate was made acidic with conc.hydrochloric acid and extracted with ethyl acetate. To remove the excesssulfur, this solution was extracted with a solution of sodium carbonate,filtered, acidified and extracted again with ethyl acetate. The extractwas dried (MgSO₄) and the solvent evaporated.

[0511] The residual 4,4′-dithiobis-(2-trifluoromethylphenoxyacetic acid) was refluxed with ethanol (1500 mL) and conc. sulphuric acid (30 mL)for 8 h and then ethanol was evaporated. The residue was dissolved inbenzene and the solution was washed with water and the solventevaporated. The residue was purified by chromatography on silica gel(250 g, benzene/chloroform) yielding 42.0 g (45%) of diethyl ester, m.p.118-120° C.

[0512] Step 3:

[0513] The above diethyl ester (20.0 g, 358 mmol) was dissolved indimethylacetamide (100 mL), sodium borohydride (3.5 g, 926 mmol) wasadded portionwise at 5° C. and the mixture was stirred for 60 min.Acetone (20 mL) and benzene (300 mL) were added, the mixture was washedwith water and the organic layer was evaporated. The residue wasfractionated at reduced pressure to yield the title compound (7.5 g,37%), b.p. 72° C./5 Pa. A considerable amount of high-boiling materialremained (starting diethyl ester).

[0514] R_(F) (SiO₂, chloroform/methanol 9:1): 0.69.

[0515]¹H NMR spectrum (300 MHz, CDCl₃): 7.56 (d, J=2.2 Hz, 1 H); 7.41(dd, J=2.2 and 8.5 Hz, 1 H); 6.78 (d, J=8.5 Hz, 1 H); 4.68 (s, 2 H);4.25 (q, J=7.15 Hz, 2 H); 3.46 (s, 1 H); 1.27 (t, J=7.15 Hz, 3 H).

[0516] Intermediate 12

(2-Chloro-4-mercapto-phenoxy)-acetic acid ethyl ester

[0517]

[0518] Step 1:

[0519] A mixture of 2-chloro-4-nitrophenol (63.6 g, 0.367 mol), ethylbromoacetate (67.0 g, 0.4 mol), potassium carbonate (60.7 g, 0.44 mol)and 2-butanone (400 mL) was refluxed under stirring for 10 h, thenfiltered and the solvent was evaporated. The residue was fractionatedyielding 61.1 g (64%) of 2-chloro-4-nitrophenoxyacetic acid ethyl ester,b.p. 150° C./40 Pa.

[0520] Step 2:

[0521] The above ester (61.1 g, 0.236 mol) was dissolved in ethanol (300mL), 5% Pd/C (4.0 g) was added and the mixture was hydrogenated atatmospheric pressure and laboratory temperature for 3 h. The catalystwas removed by filtration, ethanol was evaporated and the residual4-amino-2-chloro-phenoxyacetic acid ethyl ester (54.1 g, 0.236 mol) wasadded to the mixture of conc. hydrochloric acid (50 mL) and water (125mL) and the mixture was cooled to 5° C. A solution of sodium nitrite(16.3 g, 0.236 mol) in 70 mL water was added dropwise together withcracked ice to keep the temperature below 5° C. This takes about 5 min.

[0522] In another beaker, water (75 mL) was warmed to reflux andNa₂S.3H₂O (33.0 g, 0.26 mol) and powdered sulfur (8.3 g, 0.26 mol) wereadded and dissolved by heating and stirring. A solution of sodiumhydroxide (9.5 g, 0.236) mol in water (25 mL) was then added and themixture was cooled below 5° C. The solution of diazonium salt was addedto this solution along with ice to prevent the temperature rising. Whenaddition was complete, the mixture was allowed to warm up to roomtemperature overnight and filtered. The filtrate was made acidic withconc. hydrochloric acid and extracted with ethyl acetate. To remove theexcess sulfur, this solution was extracted with a solution of sodiumcarbonate, filtered, acidified and extracted again with ethyl acetate.The extract was dried (MgSO₄) and the solvent evaporated.

[0523] The residual 4,4′-dithiobis-(2-chlorophenoxyacetic acid) (41.5 g)was refluxed with ethanol (1000 mL) and sulphuric acid (25 mL) for 8 hand ethanol was evaporated. Benzene was added, the mixture washed withwater and the solvent was evaporated. The residue was purified bychromatography on silica gel (250 g, benzene/chloroform) yielding 17.7 g(40%) of2-chloro-4-(3-chloro-4-ethoxycarbonylmethoxy-phenyldisulfanyl)-phenoxy]-aceticacid diethyl ester.

[0524] Step 3:

[0525] The above diethyl ester (13.4 g, 273 mmol) was dissolved in 70 mLdimethylacetamide, sodium borohydride (3.1 g, 820 mmol) was addedportionwise at 5° C. and the mixture was stirred for 30 min. Acetone (15mL) and benzene (200 mL) were added, The solution was washed with water,the organic layer was evaporated and the residue fractionated at reducedpressure. This afforded (2.5 g, 19%) of the title compound, b.p. 120°C./10 Pa. A considerable amount of high-boiling material remained(starting diethyl ester).

[0526] R_(F) (SiO₂, chloroform/methanol 9:1): 0.73.

[0527]¹H NMR spectrum (300 MHz, CDCl₃): 7.35 (d, J=2.2 Hz, 1 H); 7.12(dd, J=2.2 and 8.5 Hz, 1 H); 6.72 (d, J=8.5 Hz, 1 H); 4.65 (s, 2 H);4.24 (q, J=7.15 Hz, 2 H); 3.41 (s, 1 H); 1.27 (t, J=7.15 Hz, 3 H).

[0528] Intermediate 13

(2-Chloro-4-mercapto-phenylsulfanyl)-acetic acid ethyl ester

[0529]

[0530] Step 1:

[0531] 4-Amino-2-chloro-phenylthioacetic acid hydrate (109.3 g, 0.49mol, prepared according FR Pat. 1489916) was added to the mixture ofconc. hydrochloric acid (100 mL) and water (200 mL) and the mixture wascooled to 5° C. A solution of sodium nitrite (34.5 g, 0.5 mol) in water(150 mL) was added dropwise together with cracked ice to keep thetemperature below 5° C. This takes about 5 min. In another beaker, 200mL water was heated to boil and Na₂S.9H₂O (72.6 g, 0.55 mol) andpowdered sulfur (17.0 g, 0.53 mol) were dissolved by heating andstirring. A solution of sodium hydroxide (20 g, 0.5) mol in water (50mL) was then added and the mixture cooled below 5° C. The solution ofdiazonium salt was added to this solution along with ice to prevent thetemperature rising. When addition was complete, the mixture was allowedto warm up to room temperature overnight and filtered. The filtrate wasmade acidic with conc. hydrochloric acid and extracted with ethylacetate. To remove the excess sulfur, this solution was extracted with asolution of sodium carbonate, filtered, acidified and extracted againwith ethyl acetate. The extract was dried (MgSO₄) and the solvent wasevaporated. The mixture of this residual crude4,4′-dithiobis-(2-chlorophenylthioacetic acid) (49 g), ethanol (500 mL)and conc. sulphuric acid (30 mL) was refluxed for 8 h. Ethanol wasevaporated, the residue was dissolved in diethyl ether and the solutionwas washed with water, 5% solution of sodium hydrogen carbonate and thesolvent was evaporated in vacuo. The residue was purified bychromatography on silica gel (250 g, benzene/chloroform). Yield ofdiethyl ester was 29 g (23%).

[0532] Intermediate 14 (General Procedure A)

3-[4′-(3-Hydroxy-propyl)-biphenyl-4-yl]-propan-1-ol

[0533]

[0534] Step A-B:

[0535] A mixture of 3,3′-dichloro-4,4′-diiodobiphenyl (44.5 g, 95 mmol;prepared according to J.Chem.Soc. 85, 7 (1904)), triphenylphosphine (2.0g, 7.6 mmol), palladium(II)acetate (0.67 g, 3 mmol), methyl acrylate(25.8 g, 300 mmol) and triethylamine (18.0 g, 178 mmol) inN,N-dimethylformamide (90 mL) was stirred and heated to 110° C. for 9 hand then allowed to stand overnight. The crystals of contaminated3,3′-dichlorobiphenyl-4,4′-diacrylic acid di-methyl ester were filtered,washed with water and benzene and dried.

[0536] Crude yield: 22.5 g.

[0537] Step C:

[0538] The mixture of the above crude diester (22.5 g), dioxane (300 mL)and 5% aqueous solution of sodium hydroxide (150 mL) was refluxed for 4h. Dioxane was evaporated and the residue was dissolved in water (900mL). Palladium (5% on charcoal, 4.3 g) was added and the mixture washydrogenated at atmospheric pressure and ambient temperature for 6 h.The catalyst was filtered off, contaminated biphenyl-4,4′-dipropionicacid was precipitated by the addition of conc. hydrochloric acid,filtered, washed with water and dried.

[0539] Crude yield: 15.0 g.

[0540] The above crude acid (14.1 g) was dissolved in tetrahydrofuran(150 mL), sodium borohydride (4.35 g, 115 mmol) was added portionwiseduring 30 min followed by dropwise addition of boron trifluorideetherate (22.0 g, 155 mmol). The mixture was refluxed for 8 h, quenchedwith 5% aqueous solution of sodium hydroxide (100 mL) and extracted withether (4×25 mL). The organic layer was dried with anhydrous potassiumcarbonate, evaporated and the residue was crystallized from methanolgiving pure 4,4′-biphenyidipropanol.

[0541] Yield: 5.1 g (20%, calculated on3,3′-dichloro-4,4′-diiodobiphenyl). M.p. 154-158° C.

[0542]¹H NMR spectrum (CDCl₃) 7.51 (d, J=8.1 Hz, 4 H); 7.26 (d, J=8.1Hz, 4 H); 3.71 (t, J=6.5 Hz, 4 H); 2.75 (t, J=8.0 Hz, 4 H); 1.95 (m, 4H).

[0543] Intermediate 15

(4-Mercapto-2-methoxyphenoxy)acetic acid methyl ester

[0544]

[0545] Step 1:

[0546] To a solution of (2-methoxy-4-nitrophenoxy)acetic acid ethylester (107.0 g, 0.42 mol, prepared as described in J.Chem.Soc. 1955,3681) in ethanol (800 mL) a slurry of 5% palladium (5.0 g) on carbon inethanol (50 mL) was added. The mixture was hydrogenated in a Parrapparatus for 3 h. Removal of the catalyst and solvent left oily crude(4-amino-2-methoxyphenoxy)acetic acid ethyl ester.

[0547] Yield: 93.7 g, 99%.

[0548] Step 2:

[0549] The above crude ester (91.7 g, 0.405 mol) was added to a mixtureof conc. hydrochloric acid (78 mL) and water (195 mL) and the resultingmixture was cooled to 5° C. A solution of sodium nitrite (27.0 g, 0.391mol) in water (100 mL) was added dropwise together with cracked ice tokeep the reaction temperature below 5° C. (5 min). The solution of diazocompound was stirred for 30 min and then added dropwise to a solution ofpotassium ethyl xanthogenate (90 g, 0.56 mol) in water (100 mL)maintaining the reaction temperature between 45 and 50° C. The mixturewas stirred for 2 h, cooled and extracted with ether (4×50 mL). Thecombined organic layers were evaporated and the residue dissolved inethanol (300 mL). Potassium hydroxide pellets (100 g, 1.79 mol) wereadded to this warm solution so quickly to maintain reflux which was thencontinued for 8 h. Ethanol was evaporated, the residue dissolved inwater, made acidic with conc. hydrochloric acid and extracted with ethylacetate (3×75 mL). The collected extracts were dried with anhydrousmagnesium sulfate and evaporated in vacuo. The obtained residue wascrystallized from chloroform yielding hemihydrate of4-mercapto-2-methoxyphenoxyacetic acid.

[0550] Yield: 22.5 g (25%). M.p. 138-140° C.

[0551]¹H NMR spectrum (CDCl₃):6.86 (m, 2 H); 6.78 (d, J=8.8 Hz, 1 H);4.66 (s, 2 H); 3.87 (s, 3 H); 3.45 (s, 1 H).

[0552] Step 3:

[0553] A solution of the above acid (20 g, 0.09 mol) methanol (200 mL)was saturated with gaseous hydrogen chloride for 1 h. The resultingmixture was refluxed for 8 h and subsequently evaporated in vacuo. Ether(100 mL) was added and the solution was washed with water (2×20 mL) and5% aqueous solution of sodium hydrogen carbonate (2×20 mL). Thecollected organic layers were dried with anhydrous sodium sulfate,evaporated in vacuo and the residue was distilled at reduced pressureyielding the title compound.

[0554] Yield: 10 g (49%) R_(F) (SiO₂, hexane/ethyl acetate, 70:30) 0.45.

[0555]¹H NMR spectrum (300 MHz, CDCl₃): 6.83 (m, 2 H); 6.71 (d, J=8.0Hz, 1 H); 4.65 (s, 2 H); 3.85 (s, 3 H); 3.78 (s, 3 H); 3.42 (s, 1 H).

[0556] Intermediate 16

3-{4-[4-(3-Hydroxy-propyl)-2-trifluoromethyl-phenylsulfanyl]-3-trifluoromethyl-phenyl)-propan-1-ol

[0557]

[0558] Step 1:

[0559] A solution of sodium sulfide nonahydrate (300 g, 1.25 mol) inwater (300 mL) was added to the mixture of4-chloro-3-trifluoromethylnitrobenzene (113 g, 0.5 mol) and 250 mL waterdropwise at 100° C. The reaction mixture was heated under stirring fornext 6 h. The oily phase was decanted, dissolved in benzene and thesolvent evaporated in vacuo to yield 75.6 oily residue. This oil (66.4g) was dissolved in ethanol (300 mL), hydrazine hydrate (25 g),activated charcoal (5 g) and ferric chloride hexahydrate (1.0 g) wereadded and the mixture was refluxed for 32 h, then filtered andevaporated. The residue was submitted to chromatography on silica gel(Fluka 60, 400 g). An elution with benzene afforded 22.6 g of4-amino-2-trifluoromethylbenzenethiol, m.p. 35-36.5° C.

[0560]¹H NMR spectrum (300 MHz, CDCl₃): 7.22 (d, J=8.5 Hz, 1 H); 6.95(d, J=2.75 Hz, 1 H); 6.72 (dd, J=2.75 and 8.5 Hz, 1 H); 3.83 (bs, 3 H).

[0561] Continuing of chromatography with chloroform afforded 35.4 g of4,4′-diamino-2,2′-bis(trifluoromethyl)diphenylsulfide, m.p. 65-70° C.

[0562]¹H NMR spectrum (300 MHz, CDCl₃): 7.05 (m, 4 H); 6.72 (d, J=8.5Hz, 2 H); 4.25 (bs, 4 H).

[0563] Step 2:

[0564] A solution of sodium nitrite (12.2 g, 177 mmol) in 30 mL waterwas added dropwise with stirring to a mixture of the above sulfide (33.5g, 95 mmol), conc. hydrochloric acid (100 mL) and cracked ice (150 g) at0° C. The resulting cold bis-diazonium salt solution was added slowly toa stirred solution of potassium iodide (90 g, 338 mmol) in 300 mL water.Benzene (300 mL) was added and after stirring the mixture at ambienttemperature for 3 h the layers was separated. The organic layer waswashed with 5% sodium hydrogen sulfite, dried and evaporated to yield 50g (91%) of 4,4′-diiodo-2,2′-bis(trifluoromethyl)diphenylsulfide.

[0565] M.p. 75-87° C. This product was used in the next step withoutpurification.

[0566] General Procedure A:

[0567] Step A-B:

[0568] A mixture of the above sulfide (49.7 g, 86.6 mmol),triphenylphosphine (1.8 g, 6.9 mmol), palladium(II)acetate (0.6 g, 2.67mmol), methyl acrylate (22.1 g, 257 mmol) and triethylamine (17 g, 168mmol) in 80 mL dimethylformamide was stirred and heated to 110° C. for 9h. After standing overnight water and benzene were added, the organiclayer was separated, washed with water, evaporated and the residue waspurified by chromatography on silica gel (Fluka, 300 g, benzene andchloroform). The yield of3-{4-[4-(2-carboxyvinyl)-2-trifluoromethyl-phenylsulfanyl]-3-trifluoromethyl-phenyl}-acrylicacid dimethyl ester was 20.1 g (47%).

[0569] M.p. 169-174° C.

[0570]¹H NMR spectrum (300 MHz, CDCl₃): 7.86 (d, J=1.6 Hz, 2 H); 7.65(d, J=16.2 Hz, 2 H); 7.54 (dd, J=1.6 and 8.25 Hz, 2 H); 7.24 (d, J=8.25Hz, 2 H); 6.48 (d, J=16.2 Hz, 2 H); 3.82 (s, 6 H).

[0571] Step C:

[0572] Step 1:

[0573] The mixture of the above ester (14.1 g, 28.8 mmol) in 100 mLmethanol and 20% sodium hydroxide (25 mL) was heated to reflux and thenstirred without heating for 4 h. Methanol was evaporated, the residuewas dissolved in water, acidified with conc. hydrochloric acid and theprecipitate filtered and dried. The yield of3-{4-[4-(2-carboxyvinyl)-2-trifluoromethyl-phenylsulfanyl]-3-trifluoromethyl-phenyl}-acrylicacid was 13.3 g (quant.).

[0574] M.p. 227-247° C.

[0575]¹H NMR spectrum (300 MHz, DMSO): 12.25 (bs, 2 H); 8.17 (s, 2 H);7.96 (d, J=8.0 Hz, 2 H); 7.66 (d, J=16.2 Hz, 2 H); 7.28 (d, J=8.0 Hz, 2H); 6.68 (d, J=16.2 Hz, 2 H).

[0576] Step 2:

[0577] The above acid (7.2 g, 156 mmol) was dissolved in 200 mL ethanol,hydrazine hydrate (40 mL) was added and then a solution of sodium(meta)periodate (15.0 g, 70 mmol) in 80 mL water was added dropwise atroom temperature during 5 h. The mixture was filtered, diluted withwater, acidified with conc. hydrochloric acid and extracted withchloroform. The organic extract was dried (MgSO₄), evaporated and theresidue was purified by chromatography on silica gel (Fluka 60, 85 g,chloroform/diethyl ether) yielding 4.5 g (62%) of3-{4-[4-(2-carboxy-ethyl)-2-trifluoromethyl-phenylsulfanyl]-3-trifluoromethyl-phenyl}-propionicacid.

[0578] M.p. 175-178° C.

[0579]¹H NMR spectrum (300 MHz, DMSO-d₆): 12.20 (s, 2 H); 7.71 (s, 2 H);7.48 (d, J=8.2 Hz, 2 H); 7.13 (d, J=8.2 Hz, 2 H); 2.87 (t, J=7.4 Hz, 4H); 2.56 (t, J=7.4 Hz, 4 H).

[0580] Step 3:

[0581] The above acid (4.4 g, 9.4 mmol)) was dissolved in 50 mLtetrahydrofuran, sodium borohydride (0.80 g, 21.1 mmol) was addedportionwise during 30 min and then boron trifluoride etherate (4.9 g,34.5 mmol) dropwise. The mixture was diluted with diethyl ether (100 mL)and then stirred at laboratory temperature for 48 h. The reactionmixture was quenched with 10% hydrochloric acid, the organic layer wasdried (K₂CO₃) and evaporated to give 4.1 g (99%) of3-{4-[4-(3-hydroxy-propyl)-2-trifluoromethyl-phenylsulfanyl]-3-trifluoromethyl-phenyl}-propan-1-ol.

[0582] M.p. 96-102° C.

[0583]¹H NMR spectrum (300 MHz, CDCl₃): 7.55 (s, 2 H); 7.24 (dd, 2 H);7.13 (d, J=8.0 Hz, 2 H); 3.68 (t, 4 H); 2.75 (t, J=7.8 Hz, 4 H); 1.89(m, 4 H); 1.60 (bs,1 H); 1.38 (bs, 1 H).

Example 1 General Procedure E2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-methoxycarbonyl-ethyl)-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-phenyl]-propionicacid methyl ester

[0584]

[0585] Step C-D:

[0586] To a stirred solution of2-({6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethanol(intermediate 4) (38 mg, 0.17 mmol) in dry THF (3.5 ml) was added at 0°C. under nitrogen tributylphosphine (100 mg, 0.50 mmol) and2-ethoxy-3-(4-mercapto-phenyl)-propionic acid methyl ester (intermediate2) (98 mg, 0.41 mmol). The reaction mixture was stirred for 15 min. andazodicarboxylic dipiperidine (126 mg, 0.50 mmol) was added. The reactionwas stirred for 6 h, after which water (5 ml) was added and the mixturewas extracted with methylene chloride (3×20 ml). The combined organicphases were dried (MgSO₄), filtered and evaporated. The crude productwas purified on column chromatograph using heptanes: ethyl acetate (3:1)as eluent to give the title compound in 85 mg (75%) yield.

[0587]¹H NMR (300 MHz, CDCl₃): δ 7.3-7.2 (m, 5H); 7.15 (d, J=8 Hz, 4H);5.72 (d, J=8 Hz, 2H); 4.01 (t, J=6 Hz, 2H); 3.71 (s, 6H); 3.7-3.55 (m,6H); 3.40-3.27 (m, 2H); 3.10 (t, J=7 Hz, 4H); 2.98 (m, 4H); 2.95 (s,6H); 1.15 (t, J=6 Hz, 6H).

Example 2 General Procedure D3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-2-chloro-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-3-chloro-phenyl]-2-ethoxy-propionicacid

[0588]

[0589] Step A:

[0590]2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-methoxycarbonyl-ethyl)-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-phenyl]-propionicacid methyl ester (example 1) (85 mg, 0.13 mmol) was dissolved inethanol (5 ml) by heating to 60° C. 1N aqueous NaOH was added to thewarm solution and the reaction mixture was stirred at 60° C. for 5 h.The reaction mixture was evaporated and the residue suspended in water(2 ml). The suspension was extracted with methylene chloride (2×25 ml),and the combined organic phases were dried, filtered and evaporated togive the title compound in 71 mg (86%) yield.

[0591]¹H NMR (300 MHz, CDCl₃): δ 7.26 (m, 5H); 7.15 (d, J=8 Hz, 4H);5.73 (d, J=8 Hz, 2H); 4.05 (m, 2H); 3.74-3.55 (m, 6H); 3.46-3.34 (m,2H); 3.12-2.94 (m, 8H); 2.93 (s, 6H); 1.15 (t, J=6 Hz, 6H).

Example 3 General Procedure E(5′-{2-[(6-{[2-(2′-Ethoxycarbonylmethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid ethyl ester

[0592]

[0593] Step C-D:

[0594] Was synthesized as described under example 1, step C-D, usingethyl 2,6-diphenyl-4-hydroxyphenoxyacetate (intermediate 3) (143 mg,0.41 mmol) in stead of 2-ethoxy-3-(4-mercapto-phenyl)-propionic acidmethyl ester giving the title compound in 26 mg (17%) yield.

[0595]¹H NMR (300 MHz, CDCl₃): δ 7.58 (m, 8H); 7.43-7.27 (m, 13H); 6.85(s, 4H); 5.83 (d, J=8 Hz, 2H); 4.20 (t, J=6 Hz, 4H); 5.93 (m, 8H); 5.73(s, 4H); 3.07 (s, 6H); 1.06 (t, J=7 Hz).

Example 4 General Procedure D(5′-{2-[(6-{[2-(2′-Carboxymethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy)-[1,1′,3′,1″]terphenyl-2′-yloxy)-aceticacid

[0596]

[0597] Step A:

[0598] Was synthesized as described under example 2, step A from(5′-{2-[(6-{[2-(2′-ethoxycarbonylmethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid ethyl ester (example 3) in 15 mg (60%) yield.

[0599]¹H NMR (300 MHz, CDCl₃): δ 7.60-7.25 (m, 21 H); 6.84 (s, 4H); 5.86(d, J=8 Hz, 2H); 4.19 (t, J=6 Hz, 4 H); 3.92 (t, J=6 Hz, 4H); 3.72 (s,4H); 3.10 (s, 6H).

Example 5 General Procedure E(S,S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-methoxycarbonyl-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl)-methyl-amino)-ethoxy]-phenyl}-propionicacid methyl ester

[0600]

[0601] Step C-D:

[0602] Was synthesized as described under example 1, step C-D, using(S)-2-(2-benzoyl-phenylamino)-3-(4-hydroxy-phenyl)-propionic acid methylester (J. Med. Chem. 1998, 41, 5020-5036) (154 mg, 0.41 mmol) in steadof 2-ethoxy-3-(4-mercapto-phenyl)-propionic acid methyl ester giving thetitle compound in 46 mg (29%) yield.

[0603]¹H NMR (300 MHz, CDCl₃): δ 8.91 (d, J=7 Hz, 2H); 7.60 (d, J=7 Hz,4H); 7.55-7.25 (m, 11H); 7.15 (d, J=8 Hz, 4H); 6.76 (d, J=8 Hz, 4H);6.56-6.53 (m, 4H); 5.80 (d, J=8 Hz, 2H); 4.37 (q, J=6 Hz, 2H); 4.08 (t,J=6 Hz, 4H); 3.87 (t, J=6 Hz, 4H); 3.67 (s, 6H); 3.24-3.06 (m, 4H); 3.05(s, 6H).

Example 6 General Procedure D(S,S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-carboxy-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-propionicacid

[0604]

[0605] Step A:

[0606] Was synthesized as described under example 2, step A from(S,S)-2-(2-benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-methoxycarbonyl-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)ethoxy]-phenyl}-propionicacid methyl ester (example 5) in 42 mg (93%) yield.

[0607]¹H NMR (300 MHz, CDCl₃): δ 8.80 (br. s, 2H); 7.62-7.27 (m, 15 H);7.10 (t, J=7 Hz, 4H); 6.72 (d, J=8 Hz, 6H); 6.60 (q, J=7 Hz, 2H); 5.84(d, J=8 Hz, 2H); 4.48 ( br s, 2H); 4.08 (t, J=6 Hz, 4H); 3.95 (t, J=6Hz, 4H); 3.30-3.12 (m, 4H); 3.04 (d, J=5 Hz, 6H).

Example 7 General Procedure E(3-Chloro-4-{2-[(6-{[2-(2-chloro-4-ethoxycarbonylmethyl-phenoxy)-ethyl}-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid ethyl ester

[0608]

[0609] Step C-D:

[0610] Was synthesized as described under example 1, step C-D, using(3-chloro-4-hydroxy-phenyl)-acetic acid ethyl ester (US 6,090,836) (88mg, 0.41 mmol) in stead of 2-ethoxy-3-(4-mercapto-phenyl)-propionic acidmethyl ester giving the title compound in 45 mg (43%) yield.

[0611]¹H NMR (300 MHz, CDCl₃): δ 7.32-7.00 (m, 5H); 6.75 (d, J=8 Hz,2H); 5.83 (d, J=8 Hz, 2H); 4.15 (m, 8H); 3.97 (t, J=6 Hz); 5.50 (s, 4H);3.14 (s, 6H); 1.24 (t, J=6 Hz

Example 8 General Procedure D(4-{2-[(6-{[2-(4-Carboxymethyl-2-chloro-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-3-chloro-phenyl)-aceticacid

[0612]

[0613] Step A:

[0614] Was synthesized as described under example 2, step A from(3-chloro-4-{2-[(6-{[2-(2-chloro-4-ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid ethyl ester (example 7) in 90 mg (73%) yield.

[0615]¹H NMR (300 MHz, CDCl₃): δ 7.25 (m, 2H); 7.10-6.93 (m, 5H); 6.68(d, J=8 Hz, 2H); 5.82 (d, J=8 Hz, 2H); 4.15 (t, J=6 Hz, 4H); 3.98 (t,J=6 Hz, 4H); 3.50 (s, 4H);

Example 9 General Procedure E(3-{2-[(6-{[2-(3-Ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid ethyl ester

[0616]

[0617] Step C-D:

[0618] Was synthesized as described under example 1, step C-D, using(3-hydroxy-phenyl)-acetic acid ethyl ester (U.S. Pat. No. 6,090,836) (74mg, 0.41 mmol) in stead of 2-ethoxy-3-(4-mercapto-phenyl)-propionic acidmethyl ester giving the title compound in 30 mg (32%) yield.

[0619]¹H NMR (300 MHz, CDCl₃): δ 7.34-7.14 (m, 3H); 6.87-6.70 (m, 6H);5.84 (d, J=8 Hz, 2H); 4.15 (m, 8H); 3.93 (t, J=6 Hz, 4H); 3.54 (s, 4H);3.10 (s, 6H); 1.24 (t, J=7 Hz, 6H).

Example 10 General Procedure D(3-{2-[(6-{[2-(3-Carboxymethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid

[0620]

[0621] Step A:

[0622] Was synthesized as described under example 2, step A using(3-{2-[(6-{[2-(3-ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid ethyl ester (example 9) in 26 mg (88%) yield.

[0623]¹H NMR (300 MHz, CDCl₃): δ 7.28-1.14 (m, 3H); 6.80 (m, 6H); 5.82(d, J=8 Hz, 2H); 4.12 (t, J=6 Hz, 4H); 3.93 (t, J=6 Hz, 4H); 3.57 (s,4H); 3.13 (s, 6H).

Example 11 General Procedure E(S,S)-2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-propionicacid ethyl ester

[0624]

[0625] Step C-D:

[0626] Was synthesized as described under example 1, step C-D, using(S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl ester (501 mg,2.11 mmol) in stead of 2-ethoxy-3-(4-mercapto-phenyl)-propionic acidmethyl ester giving the title compound in 106 mg (30%) yield.

[0627]¹H NMR (300 MHz, CDCl₃): δ 7.29 (t, J=8 Hz, 1H); 7.12 ( d, J=8 Hz,4H); 6.77 (d, H=8 Hz, 4H); 5.82 (d, J=8 Hz, 2H); 4.14 (m, 8H); 5.93 (m,6H); 3.60 (m, 2H); 3.35 (m, 2H); 3.07 (s, 6H); 2.94 (d, J=7 Hz, 4H);1.22 (t, J=7 Hz, 6H); 1.14 (t, J=7 Hz, 6 H).

Example 12 General Procedure D(S,S)-3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-2-ethoxy-propionicacid

[0628]

[0629] Step A:

[0630] Was synthesized as described under example 2, step A using(S,S)-2-ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-propionicacid ethyl ester (example 11) in 91 mg (93%) yield.

[0631]¹H NMR (300 MHz, CDCl₃): δ 7.29 (t, J=7 Hz, 1 H); 7.09 (d, J=8 Hz,4H); 6.75 (d, J=8 Hz, 4H); 5.80 ( d, J=7 Hz, 2 H); 4.12 ( t, J=6 Hz,4H); 4.04 (t, J=7 Hz, 2H); 3.94 (t, J=7 Hz, 4H); 3.62 (m, 2H); 3.42 (m,2H); 3.07 (s, 6H); 3.05-2.92 (m, 4H); 1.17 (t, J=7 Hz, 6 H).

Example 13 General Procedure A(S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid isopropyl ester

[0632]

[0633] Step D-E:

[0634] To a stirred solution of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol(intermediate 5) (102 mg, 0.25 mmol) in dry THF (10 ml) was added at 0°C. under nitrogen triphenylphosphine (252 mg, 1.0 mmol) and(S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid isopropyl ester (252mg,1.0 mmol). The reaction mixture was stirred for 15 min. anddiethylazodicarboxylate (174 mg, 1.0 mmol) was added. The reaction wasstirred for 6 h, after which water (10 ml) was added and the mixture wasextracted with methylene chloride (3×20 ml). The combined organic phaseswere dried (MgSO₄), filtered and evaporated. The crude product waspurified on column chromatograph using methylene chloride:THF (100:1) aseluent to give the title compound in 150 mg (69%) yield.

[0635]¹H NMR (400 MHz, CDCl₃): δ 7.57 (s, 2H); 7.37 (d, J=8 Hz, 2H);7.18 (m, 6H); 6.83 (d, J=8 Hz, 4H); 5.04 (m, 2H); 3.98 (m, 6H); 3.61 (m,2H); 3.36 (m, 2H); 2.93 (m, 8H); 2.15 (m, 4H); 1.25 (d, J=6 Hz, 12 H);1.17 (t, J=6 Hz, 6H).

Example 14 General Procedure D(S,S)-3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid

[0636]

[0637] Step A:

[0638] To a solution of(S,S)-2-ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid isopropyl ester (example 13) in ethanol (4 ml) was added 1 N NaOH(0.6 ml) at room temperature. The reaction was stirred for 48 hours atroom temperature and evaporated. The residue was treated with 1 N HCland extracted with methylene chloride (2×15 ml). The combined organicphases were dried and evaporated to give the title compound in 105 mg(78%) yield.

[0639]¹H NMR (400 MHz, CDCl₃): δ 7.56 (s, 2H); 7.47 (d, J=8 Hz; 2H);7.18 (m, 6H); 6.84 (d, J=8 Hz, 4H); 4.05 (m, 2H); 4.00 (t, J=6 Hz, 4H);3.63 (m, 2H); 3.41 (m, 2H); 3.07 (m, 2H); 2.96 (m, 2H); 2.91 (t, J=6 Hz,4H); 2.15 (m, 4H); 1.17 (t, J=6 Hz, 6H).

Example 15 General Procedure A(S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid isopropyl ester

[0640]

[0641] Step D-E:

[0642] Was synthesized as described under example 13 step C-A using3-[4′-(3-hydroxy-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol(intermediate 6) (102 mg, 0.25 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olgiving the title compound in 205 mg (93%) yield.

[0643]¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 2H); 7.67 (d, J=8 Hz, 2H);7.45 (d, J=8 Hz, 2H); 7.16 (d, J=8 Hz, 4H); 6.84 (d, J=8 Hz, 4H); 5.04(m, 2H); 4.01 (t, J=6 Hz, 4H); 3.96 (t, J=6 Hz, 2H); 3.61 (m, 2H); 3.37(m, 2H); 3.04 (t, J=6 Hz, 4H); 2.95 (d, J=6 Hz, 4H); 2.14 (m, 4H);1.28-1.13 (m, 18 H).

Example 16 General Procedure D(S,S)-3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid

[0644]

[0645] Step A:

[0646] Was synthesized as described under example 14 step A using(S,S)-2-ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid isopropyl ester (example 15) to give the title compound in 167 mg(90%) yield.

[0647]¹H NMR (400 MHz, CDCl₃): δ 7.83 (s, 2H); 7.67 (d, J=8 Hz, 2H);7.45 (d, J=8 Hz, 2H); 7.18 (d, J=8 Hz, 4H); 6.85 (d, J=8 Hz, 4H); 4.04(m, 6H); 3.64 (m, 2H); 3.44 (m, 2H); 3.12-2.93 (m, 8H); 2.14 (m, 4H);1.19 (t, J=6 Hz, 6H).

Example 17 General Procedure A(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl)-2-ethoxy-propionicacid iso-propyl ester

[0648]

[0649] Step D-E:

[0650] Was synthesized as described under example 13 step D-E using(S)-3-(3-bromo-4-hydroxy-phenyl)-2-ethoxy-propionic acid isopropyl ester(intermediate 7) (331 mg, 1.0 mmol) instead of2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid isopropyl ester to give thetitle compound 160 mg (62%) yield.

[0651]¹H NMR (400 MHz, CDCl₃): δ 7.58 (s, 2H); 7.45 (s, 2H); 7.40 (d,J=8 Hz, 2H); 7.19 (d, J=8 Hz, 2H); 7.14 (d, J=8 Hz, 2H); 6.78 ( d, J=8Hz, 2H); 5.05 (m, 2H); 4.04 (t, J=6 Hz. 4H); 3.94 ( t, J=6 Hz, 2H); 3.63(m, 2H); 3.37 (m, 2H); 2.99 (t, J=6 Hz, 4H); 2.93 (d, J=6 Hz, 4H); 2.20(m, 4H); 1.27-1-14 (m, 18H).

Example 18 General Procedure D(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid

[0652]

[0653] Step A:

[0654] Was synthesized as described under example 14 step A using(S,S)-3-{3-bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid isopropyl ester (example 17) to give the title compound in 112 mg(76%) yield.

[0655]¹H NMR (400 MHz, CDCl₃): δ 7.58 (s, 2H); 7.47 (s, 2H); 7.39 (d,J=8 Hz, 2H); 7.20 (d, J=8 Hz, 2H); 7.15 (d, J=8 Hz, 2H); 6.78 (d, J=8Hz, 2H); 4.02 (m, 6H); 3.65 (m, 2H); 3.40 (m, 2H); 3.08-2.90 (m, 8H);2.20 (m, 4H); 1.19 (t, J=6 Hz, 6H).

Example 19 General Procedure A(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl{-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid iso-propyl ester

[0656]

[0657] Step D-E:

[0658] Was synthesized as described under example 17 step D-E using3-[4′-(3-hydroxy-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol(intermediate 6) (102 mg, 0.25 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olgiving the title compound in 132 mg (51%) yield.

[0659]¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 2H); 7.67 (d, J=8 Hz, 2H);7.47 (m, 4H); 7.15 (d, J=8 Hz, 2H); 6.80 (d, J=8 Hz, 2H); 5.05 (m, 2H);4.05 (t, J=6 Hz, 4H); 3.93 (t, J=6 Hz, 2H); 3.63 (m, 2H); 3.37 (m, 2H);3.10 (t, J=7 Hz, 4H); 2.94 (d, J=6Hz, 4H); 2.17 (m, 4H); 1.28-1.14 (m,18H).

Example 20 General Procedure D(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid

[0660]

[0661] Step A:

[0662] Was synthesized as described under example 14 step A using(S,S)-3-{3-bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid isopropyl ester (example 19) to give the title compound in 95 mg(78%) yield.

[0663]¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 2H); 7.67 (d, J=8 Hz, 2H);7.49 (m, 4H); 7.15 (d, J=8 Hz, 2H); 6.82 (d, J=8 Hz, 2H); 4.05 (m, 6H);3.66 (m, 2H); 3.42 (m, 2H); 3.14-2.90 (m, 8H); 2.16 (m, 4H); 1.19 (t,J=6 Hz, 6H).

Example 21 General Procedure A(S,S)-3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid isopropyl ester

[0664]

[0665] Step D-E:

[0666] Was synthesized as described under example 17 step D-E using3-[7-(3-hydroxy-propyl)-9H-fluoren-2-yl]-propan-1-ol (intermediate 8)(85 mg, 0.30 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olgiving the title compound in 100 mg (37%) yield.

[0667]¹H NMR (400 MHz, CDCl₃): δ 7.64 (d, J=8 Hz, 2H); 7.44 (s, 2H);7.36 (s, 2H); 7.22 (d, J=8 Hz, 2H); 7.10 (d, J=8 Hz, 2H); 6.75 (d, J=8Hz, 2H); 5.50 (m, 2H); 3.99 (t, J=6 Hz, 4H); 3.94 (t, J=6 Hz, 2H); 3.82(s, 2H); 3.62 (m, 2H); 3.55 (m, 2H); 2.90 (m, 8H); 2.17-1.14 (m, 18H).

Example 22 General Procedure D(S,S)-3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid

[0668]

[0669] Step A:

[0670] Was synthesized as described under example 14 step A using(S,S)-3-{3-bromo-4-[3-(7-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid isopropyl ester (example 21) to give the title compound in 51 mg(56%) yield.

[0671]¹H NMR (400 MHz, CDCl₃): δ 7.57 (s, 2H); 7.47 (s, 2H); 7.38 (d,J=8 Hz, 2H); 7.18 (d, J=8 Hz, 2H); 7.14 (d, J=8 Hz, 2H); 6.80 (d, J=8Hz, 2H); 4.03 (t, J=6 Hz, 6H); 3.65 (m, 2H); 3.40 (m, 2H); 3.07-2.88 (m,8H); 2.19 (m, 4H); 1.19 (t, J=6 Hz, 6H).

Example 23 General Procedure A(S,S)-2-Ethoxy-3-{4-[3-(7-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-propionicacid isopropyl ester

[0672]

[0673] Step D-E:

[0674] Was synthesized as described under example 13 step D-E using3-[7-(3-hydroxy-propyl)-9H-fluoren-2-yl]-propan-1-ol (intermediate 8)(102 mg, 0.25 mmol) instead of3-[4′-3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olgiving the title compound in 100 mg (45%) yield.

[0675]¹H NMR (400 MHz, CDCl₃): 7.64 (d, J=8 Hz, 2H); 7.35 (s, 2H); 7.18(d, J=8 Hz, 2H); 7.15 (d, J=8 Hz, 4H); 6.80 (d, J=8 Hz, 4H); 5.02 (m,2H); 3.95 (m, 6H); 3.82 (s, 2H); 3.60 (m, 2H); 3.35 (m, 2H); 2.94 (d,J=7 Hz, 4H); 2.86 (t, J=7 Hz, 4H); 2.12 (m, 4H); 1.25-1.14 (m, 18H).

Example 24 General Procedure D(S,S)-3-{4-[3-(7-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid

[0676]

[0677] Step A:

[0678] Was synthesized as described under example 14 step A using(S,S)-2-ethoxy-3-{4-[3-(7-(3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl)-9H-fluoren-2-yl)-propoxy]-phenyl}-propionicacid isopropyl ester (example 23) to give the title compound in 65 mg(73%) yield.

[0679]¹H NMR (400 MHz, CDCl₃): δ 7.65 (d, J=8 Hz, 2H); 7.36 (s, 2H);7.18 (d, J=8 Hz, 2H); 7.16 (d, J=8 Hz, 4H); 6.83 (d, J=8 Hz, 4H); 4.04(m, 2H); 3.96 (t, J=6 Hz, 4H); 3.82 (s, 2H); 3.63 (m, 2H); 3.44 (m, 2H);3.06 (m, 2H); 2.96 (m, 2H); 2.86 (t, J=7 Hz, 4H); 2.12 (m, 4H); 1.17 (t,J=6 Hz, 6H).

Example 25 General Procedure A[4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester

[0680]

[0681] Step D-E:

[0682] Under nitrogen, azodicarboxylic dipiperidine (253 mg, 1.0 mmol)was added to a solution of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol(intermediate 5) (102 mg, 0,25 mmol) and tributylphosphine (203 mg, 1.0mmol) in THF (10 ml) at 0° C. The reaction mixture was stirred for 10min after which (4-mercapto-2-methyl-phenoxy)-acetic acid methyl ester(intermediate 1) (213 mg, 1.0 mmol) was added prop wise over 5 min. Thereaction mixture was stirred at 0° C. for 2 h and at room temperaturefor 1 h. Water (20 ml) was added and the reaction mixture was extractedwith methylene chloride (3×25 ml). The combined organic phases weredried (MgSO₄), filtered and evaporated to give crude product. Theresidue was purified on column chromatography using methylenechloride:THF (100:1) as eluent to give the title compound in 102 mg(51%) yield.

[0683]¹H NMR (400 MHz, CDCl₃): δ 7.51 (s, 2H); 7.35-7.14 (m, 8H); 6.64(d, J=8 Hz, 2H); 4.63 (s, 4H); 3.79 (s, 6H); 2.86 (m, 8H); 2.26 (s, 6H);1.95 (m, 4H).

Example 26 General Procedure D[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid

[0684]

[0685] Step A:

[0686] To a solution of[4-(3-{4′-[3-(4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester (example 25) (102 mg, 0.12 mmol) in ethanol (5 ml) wasadded aqueous 1N NaOH (0.5 ml). The reaction mixture was stirred for 3hours at room temperature and the evaporated. Water (10 ml) and 1 N HCl(0.6 ml) was added to the residue and the mixture was extracted withmethylene chloride (2×30 ml). The combined organic phases were dried(MgSO₄), filtered and evaporated to give the title compound in 96 mg(98%) yield.

[0687]¹H NMR (400 MHz, CDCl₃): δ 7.51 (s, 2H); 7.32 (d, J=8 Hz, 2H);7.15 (m, 6H); 6.65 (d, J=8 Hz, 2H); 4.64 (s, 4H); 2.85 (m, 8H); 2.25 (s,6H); 1.95 (m, 4H).

Example 27 General Procedure A[4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester

[0688]

[0689] Step D-E:

[0690] Was synthesized as described under example 25 step D-E using3-[4′-(3-hydroxy-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol(intermediate 6) (102 mg, 0.25 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olto give the title compound in 130 mg (65%) yield.

[0691]¹H NMR (400 MHz, CDCl₃): δ 7.77 (s, 2H); 7.65 (d, J=8 Hz, 2H);7.37 (d, J=8 Hz, 2H); 7.22 (m, 4H); 6.64 (d, J=8 Hz, 2H); 4.64 (s, 4H);3.81 (s, 6H); 2.93 (m, 8H); 2.26 (s, 6H); 1.93 (m, 4H).

Example 28 General Procedure D[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid

[0692]

[0693] Step A:

[0694] Was synthesized as described under example 26 step A using[4-(3-{4′-[3-(4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester (example 27) to give the title compound in 130 mg(96%) yield.

[0695]¹H NMR (400 MHz, MeOD): δ 7.81 (s, 2H); 7.75 (d, J=8 Hz, 2H); 7.43(J=8 Hz, 2H); 7.17 (m, 4 H); 6.75 (d, J=8 Hz, 2H); 4.64 (s, 4H); 2.90(m, 8H); 2.24 (s, 6H); 1.87 (m, 4H).

Example 29 General Procedure A[4-(3-{7-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester

[0696]

[0697] Step D-E:

[0698] Was synthesized as described under example 25 step D-E using3-[7-(3-hydroxy-propyl)-9H-fluoren-2-yl]-propan-1-ol (Intermediate 8)(85mg, 0.3 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olto give the title compound in 34 mg (17%) yield after a second columnpurification using heptane:ethyl acetate (5:2) as eluent.

[0699]¹H NMR (400 MHz, CDCl₃): δ 7.64 (d, J=8 Hz, 2H); 7.33 (s, 2H);7.15 (m, 6H); 6.70 (d, J=8 Hz, 2H); 4.63 (s, 4H); 3.82 (s, 2H); 3.80 (s,6H); 2.85 (t, J=6 Hz, 4H); 2.79 (t, J=6 Hz, 4H); 2.26 (s, 6H); 1.94 (m,4H).

Example 30 General Procedure D[4-(3-{7-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propyl-sulfanyl)-2-methyl-phenoxy]-aceticacid

[0700]

[0701] Step A:

[0702] Was synthesized as described under example 26 step A using[4-(3-{7-[3-(4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester (example 29) to give the title compound in 27 mg (73%)yield.

[0703]¹H NMR (400 MHz, DMSO): δ 7.73 (d, J=8 Hz, 2H); 7.35 (s, 2H); 7.16(m, 6H); 6.78 (d, J=8 Hz, 2H); 4.67 (s, 4H); 3.83 (s, 2H); 2.87 (t, J=6Hz, 4H); 2.75 (t, J=6 Hz, 4H); 2.16 (s, 6H); 1.84 (m, 4H).

Example 31 General Procedure A(4-{2-[2-(3-{4-[2-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid methyl ester

[0704]

[0705] Step D-E:

[0706] Was synthesized as described under example 25 step D-E using2-(2-{3-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-phenyl}-5-methyl-oxazol-4-yl)-ethanol(intermediate 9) (99 mg, 0.3 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olto give the title compound in 123 mg (57%) yield after a second columnpurification using methylene chloride:THF (50:1) as eluent.

[0707]¹H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H); 7.99 (d, J=8 Hz, 2H);7.48 (t, J=8 Hz, 1H); 7.23 (s, 2H); 7.17 (d, J=8 Hz, 2H); 6.61 (d, J=8Hz, 2H); 4.58 (s, 4H); 3.80 (s, 6H); 3.17 (t, J=7 Hz, 4H); 2.78 (t, J=7Hz, 4H); 2.32 (s, 6H); 2.24 (s, 6H).

Example 32 General Procedure D(4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

[0708]

[0709] Step A:

[0710] Was synthesized as described under example 26 step A using(4-{2-[2-(3-{4-[2-(4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid methyl ester (example 31) to give the title compound in 108 mg(92%) yield.

[0711]¹H NMR (400 MHz, CDCl₃): δ 8.37 (s,1 H); 7.95 (d, J=8 Hz, 2H);7.47 (t, J=8 Hz, 1 H); 7.16 (s, 2H); 7.06 (d, J=8 Hz, 2H); 6.54 (d, J=8Hz, 2H); 4.52 (s, 4H); 3.15 (t, J=7 Hz, 4H); 2.82 (t, J=7 Hz, 4H); 2.24(s, 6H); 2.19 (s, 6H).

Example 33 General Procedure A(S,S)-2-Ethoxy-3-[4-(2-{2-[4′-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid isopropyl ester

[0712]

[0713] Step D-E:

[0714] Was synthesized as described under example 13 step D-E using2-(2-{4′-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-biphenyl-4-yl}-5-methyl-oxazol-4-yl)-ethanol(intermediate ate 10) (101 mg, 0.25 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-olto give the title compound in 5 mg (2%) yield.

[0715]¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, J=8 Hz, 4H); 7.70 (d, J=8 Hz,4H); 7.15 (d, J=8 Hz, 4H); 6.83 (d, J=8 Hz, 4H); 5.02 (m, 2H); 4.23 (t,J=6 Hz, 4H); 3.94 (t, J=6 Hz, 2H); 3.58 (m, 2H); 3.35 (m, 2H); 2,99 (t,J=6 Hz, 4H); 2.94 (d, J=6 Hz, 4H); 2.39 (s, 6H); 1.24-1.13 (m, 18H).

Example 34 General Procedure D(S,S)-3-[4-(2-{2-[4′-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid

[0716]

[0717] Step A:

[0718] Was synthesized as described under example 26 step A using(S,S)-2-ethoxy-3-[4-(2-{2-[4′-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl)-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid isopropyl ester (example 33) to give the title compound in 4 mg(100%) yield.

[0719]¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, J=8 Hz, 4 H); 7.68 (d, J=8 Hz,4H); 7.12 (m, 4H); 6.83 (d, J=8 Hz, 2H); 6.77 (d, J=8 Hz, 2H); 4.24 (t,J=6 Hz, 4H); 4.05 (m, 2H); 3.58 (m, 2H); 3.48 (m, 2H); 3.12-2.95 (m,4H); 1.16 (t, J=6 Hz, 6H).

Example 35 General Procedure A(S,S)-2-Ethoxy-3-[4-(2-{2-[3-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl)-ethoxy)-phenyl]-propionicacid isopropyl ester

[0720]

[0721] Step D-E:

[0722] Was synthesized as described under example 13 step D-E using2-(2-{3-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-phenyl}-5-methyl-oxazol-4-yl)-ethanol(intermediate 9) (164 mg, 0.5 mmol) instead of3-[4′-(3-hydroxy-propyl)-2,2′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol to give the title compound in 313 mg (84%) yield.

[0723]¹H NMR (400 MHz, CDCl₃): δ 8.57 (s, 1H); 8.03 (d, J=8 Hz, 2H);7.47 (t, J=8 Hz, 1H); 7.14 (d, J=8 Hz, 4H); 6.82 (d, J=8 Hz, 4H); 5.02(m, 2H); 4.23 (t, J=6 Hz, 4H); 3.93 (t, J=7 Hz, 2H); 3.58 (m, 2H); 3.34(m, 2H); 2.98 (t, J=6 Hz, 4H); 2.93 (d, J=6 Hz, 4H); 2.38 (s, 6H);1.30-1.12 (m, 18H).

Example 36 General Procedure D(S,S)-3-[4-(2-{2-[3-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl-}-5-methyl-oxazol-2yl-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid

[0724]

[0725] Step A:

[0726] Was synthesized as described under example 26 step A using(S,S)-2-ethoxy-3-[4-(2-{2-[3-(4-(2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl)-5-methyl-oxazol-2yl-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid isopropyl ester (example 35) to give the title compound in 150 mg(44%) yield.

[0727]¹H NMR (400 MHz, CDCl₃): δ 8.45 (s, 1H); 7.94 (d, J=8 Hz, 2H);7.42 (t, J=8 Hz, 1H); 7.06 (d, J=8 Hz, 4H); 6.72 (d, J=8 Hz, 4H); 4.14(t, J=6 Hz, 4H); 3.94 (m, 2H); 3.32 (m, 2H); 3.02-2.81 (m, 8H); 2.26 (s,6H); 1.06 (t, J=6 Hz, 6H).

Example 37 General Procedure B[4-(3-{4′-[3-(4-Carboxymethylsulfanyl-3-chloro-phenylsulfanyl)-propyl]-3,3′-bis-rifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-chloro-phenylsulfanyl]-aceticacid

[0728]

[0729] Step A-B:

[0730] (2-Chloro-4-mercapto-phenylsulfanyl)-acetic acid ethyl ester(intermediate 13) (3.7 g, 7 mmol) was dissolved in dimethylacetamide (20mL). Sodium borohydride (0.5 g, 13.2 mmol) was added portionwise at 5°C. and the mixture was stirred for 30 min.3,3′-Bistrifluoromethyl-4,4′-biphenyidipropanol (intermediate 6)bismethanesulfonate (3.25 g, 5.8 mmol) dissolved in 2-butanone (35 mL)and potassium carbonate (1.4 g, 10 mmol) were added and the mixture wasstirred for 48 h at laboratory temperature. Water and benzene wereadded, the organic layer was separated, dried (K₂CO₃), filtered andevaporated to give a residue which was purified by chromatography onsilica gel (100 g, benzene). This afforded 3.05 g (59%) of diethyl esterof the title compound.

[0731]¹H-NMR spectrum (CDCl₃): 7.80 (d, J=1.65 Hz, 2 H); 7.66 (dd,J=1.65 and 8.2 Hz, 2 H); 7.38 (d, J=8.2 Hz, 2 H); 7.34 (m, 4 H); 7.16(dd, J=2.2 and 8.25 2 H); 4.15 (q, J=7.15 Hz, 4H); 3.63 (s, 4 H); 2.97(m, 8 H); 1.99 (pent, 4 H); 1.22 (t, J=7.15 Hz, 6 H).

[0732] General Procedure D:

[0733] Step A:

[0734] The above diethyl ester (3.0 g, 3.35 mmol) was dissolved in themixture of ethanol (30 mL) and tetrahydrofuran (30 mL), 20% sodiumhydroxide (7 mL) ) was added and the mixture was left to stand for 48 h.The solvents were evaporated, the residue was dissolved in water, themixture was acidified with hydrochloric acid and the product wasextracted with chloroform. The organic layer was dried (MgSO₄),evaporated and the residue was triturated with methanol yielding 2.17 g(72%) of the title compound as trihydrate.

[0735] M.p. 108-112° C. R_(F) (SiO₂, chloroform/ethanol 10:1) 0.40.

[0736]¹H NMR spectrum (300 MHz, DMSO-d₆): 7.91 (m, 4 H); 7.55 (d, J=7.7Hz, 2 H); 7.40 (d, J=1.65 Hz, 2 H); 7.28 (m, 4 H); 3.86 (s, 4 H); 3.07(t, J=7.15 Hz, 4 H); 2.89 (t, J=7.7 Hz, 4 H); 1.85 (m, 4 H).

Example 38 General Procedure B[4-[3-[4′-[3-(4-Carboxymethoxy-3-trifluoromethylphenylsulfanyl)propyl]biphenyl-4-yl]-propylsulfanyl]-2-trifluoromethylphenoxy]aceticacid

[0737]

[0738] Step A:

[0739] 3-[4′-(3-Hydroxy-propyl)-biphenyl-4-yl]-propan-1-ol (intermediate14) (5.0 g,18.5 mmol) was dissolved in dichloromethane (100 mL) andtriethylamine (6.0 g, 59 mmol) and subsequently methanesulfonyl chloride(4.6 g, 40 mmol) were added dropwise. The mixture was stirred overnight,washed with water (30 mL), evaporated in vacuo and the residuecrystallized from benzene giving 4,4′-biphenyidipropanolbismethanesulfonate.

[0740] Yield: 6.8 g (87%). M.p. 155.5-157° C.

[0741]¹H NMR spectrum (CDCl₃): 7.51 (d, J=8.2 Hz, 4 H); 7.25 (m, 4 H);4,26 (t, J=6.3 Hz, 4 H); 3.00 (s, 6 H); 2.79 (t, J=7.4 Hz, 4 H); 2.11(m, 4 H).

[0742] Step B:

[0743] The 4,4′-dithiobis(2-trifluoromethylphenoxyacetic acid diethylester) (intermediate 11) (4.5 9, 8 mmol) was dissolved inN,N-dimethylacetamide (20 mL), sodium borohydride (0.6 g, 15.9 mmol) wasadded portionwise at 5° C. and the mixture was stirred for 30 min. Thesolution of above bismethanesulfonate (3.1 g, 7.3 mmol) in 2-butanone(30 ml) and potassium carbonate (1.4 g, 10 mmol) were added and theresulting mixture was stirred overnight at ambient temperature and thenrefluxed for 3 h. Water (250 mL) and benzene (150 mL) were added, theorganic layer was separated, dried with anhydrous potassium carbonate,filtered and evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, benzene). This afforded of[4-[3-[4′-[3-(4-Carboxymethoxy-3-trifluoromethyl-phenylsulfanyl)propyl]biphenyl-4-yl]-propylsulfanyl]-2-trifluoromethylphenoxy]aceticacid di-ethyl ester.

[0744] Yield: 3.35 g (58%). M.p. 100.5-102.5° C. (benzene).

[0745]¹H NMR spectrum (CDCl₃): 7.61 (d, J=2.2 Hz, 2 H); 7.47 (m, 6 H);7.21 (d, J=8.3 Hz, 4 H); 6.80 (d, J=8.8 Hz, 2 H); 4.70 (s, 4 H); 4.25(q, J=7.2 Hz, 4 H); 2.88 (t, J=7.3 Hz, 4 H); 2.77 (t, J=7.2 Hz, 4 H);1.94 (m, 4 H); 1.28 (t, J=7.2 Hz, 6 H).

[0746] General Procedure D:

[0747] Step A:

[0748] The above diethyl ester (3.25 g, 4.1 mmol) was dissolved in amixture of ethanol (30 mL) and tetrahydrofuran (50 mL), 20% aqueoussolution of sodium hydroxide (5 mL) was added and the mixture was leftto stand for 48 h. The solvents were evaporated, the residue dissolvedin water and precipitated with acetic acid: The title compound wasfiltered, washed with water and dried.

[0749] Yield: 2.9 g (96%). M.p. 208-218° C.

[0750]¹H NMR spectrum (300 MHz, DMSO-d₆): 7.48-7.58 (m, 8 H); 7.21 (d,J=8.0 Hz, 4 H); 7.05 (d, J=8.5 Hz, 2 H); 4.76 (s, 4 H); 2.90 (t, J=7.2Hz, 4 H); 2.70 (t, J=7.4 Hz, 4H); 1.81 (m, 4 H).

Example 39 General Procedure B[4-[3-[4′-[3-(4-Carboxymethoxy-3-chlorophenylsulfanyl)propyl]-3,3′-bis-trifluoromethylbiphenyl-4-yl]propylsulfanyl]-2-chlorophenoxy]aceticacid

[0751]

[0752] Step A:

[0753] To a solution of3-[4′-(3-hydroxy-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol(intermediate 6) (5.4 g, 13.3 mmol) in dichloromethane (40 mL)triethylamine (2.5 g, 24.7 mmol) and methanesulfonyl chloride (2.7g,23.6 mmol) were added dropwise. The mixture was stirred overnight,diluted with dichloromethane (50 mL) and washed with water (2×15 mL).Evaporation of the organic solution gave3,3′-bistrifluoromethyl-4,4′-biphenyl-dipropanol bismethanesulfonate.

[0754] Yield: 6.6 g (88%).

[0755]¹H NMR spectrum (CDCl₃): 7.81 (s, 2 H); 7.70 (d, J=8.0 Hz, 2 H);7.44 (d, J=8.0 Hz, 2 H); 4.31 (t, J=6.1 Hz, 4 H); 3.04 (s, 6 H); 2.96(t, J=7.8 Hz, 4 H); 2.11 (m, 4 H).

[0756] Step B:

[0757] 4,4′-Dithiobis(2-chlorophenoxyacetic acid diethyl ester)(intermediate 12) (3.7 g, 7.5 mmol) was dissolved inN,N-dimethylacetamide (50 mL), sodium borohydride (0.55 g, 14.5 mmol)was added portionwise at 5° C. and the mixture was stirred for 30 min. Asolution of the above bismethanesulfonate (3.25 g, 5.8 mmol) in2-butanone (15 mL) and potassium carbonate (1.4 g, 10 mmol) were addedto the mixture and the resulting suspension was stirred overnight atambient temperature and subsequently refluxed for 3 h. Water (300 mL)and benzene (100 mL) were added, the organic layer was separated, driedwith anhydrous potassium carbonate, filtered an d evaporated in vacuo.The residue was purified by column chromatography (silica gel Fluka 60,benzene) yielded[4-[3-[4′-[3-(4-Carboxymethoxy-3-chlorophenylsulfanyl)propyl]-3,3′-bis-trifluoromethylbiphenyl-4-yl]propylsulfanyl]-2-chloro-phenoxy]aceticacid diethyl ester.

[0758] Yield: 2.86 g (60%).

[0759]¹H NMR spectrum (CDCl₃): 7.79 (d, J=1.7 Hz, 2 H); 7.65 (dd, J=1.7and 8.0 Hz, 2 H); 7.42 (d, J=2.2 Hz, 2 H); 7.37 (d, J=8.0 Hz, 2 H); 7.22(dd, J=2.2 and 8.5 Hz, 2 H); 6.78 (d, J=8.5 Hz, 2 H); 4.68 (s, 4 H);4.26 (q, J=7.2 Hz, 4 H); 2.93 (t, J=7.2 Hz, 8 H); 1.94 (m, 4 H); 1.29(t, J=7.2 Hz, 6 H).

[0760] General Procedure D:

[0761] Step A:

[0762] The above diethyl ester (2.8 g, 3.5 mmol) was dissolved inethanol (30 mL) and tetrahydrofuran (30 mL). 20% Aqueous solution ofsodium hydroxide (7 mL) was added, the mixture was left to stand for 48h and then evaporated in vacuo. The residue was dissolved in water andthe title product was precipitated with hydrochloric acid. The solidmass was filtered, washed with water and dried.

[0763] Yield: 2.3 g (85%). M.p. 143-152° C.

[0764]¹H NMR spectrum (300 MHz, DMSO-d₆): 7.89 (m, 4 H); 7.53 (d, J=7.7Hz, 2 H); 7.43 (d, J=2.2 Hz, 2 H); 7.27 (dd, J=2.2 and 8.5 Hz, 2 H);6.97 (d, J=8.5 Hz, 2 H); 4.77 (s, 4 H); 3.00 (t, J=7.1 Hz, 4 H); 2.86(m, 4 H); 1.80 (m, 4 H).

Example 40 General Procedure B[4-(3-{4′-[3-(4-Carboxymethoxy-3-chloro-phenylsulfanyl)-propyl]-biphenyl-4-yl)-propylsulfanyl)-2-chloro-phenoxy]-aceticacid

[0765]

[0766] Step B:

[0767] The 4,4 ′-dithiobis-(2-chloromethylphenoxyacetic acid diethylester) (intermediate 12) (2.5 g, 5.1 mmol) was dissolved in 20 mLN,N-dimethylacetamide, sodium borohydride (0.50 g, 13.2 mmol) was addedportionwise at 5° C. and the mixture was stirred for 30 min.4,4′-Biphenyldipropanol bismethanesulfonate (example38) (2.1 g, 4.95mmol) dissolved in 2-butanone (20 mL) and potassium carbonate (1.4 g, 10mmol) were added and the mixture was stirred overnight at ambienttemperature and then refluxed for 3 h. Water and benzene were added, theorganic layer was dried (K₂CO₃), filtered and evaporated to give aresidue which was purified by chromatography on silica gel (Fluka 60, 60g, benzene). This afforded 2.3 g (64%) of diethyl ester of the titlecompound.

[0768]¹H-NMR spectrum (CDCl₃): 7.49 (d, 4H, J=8.0); 7.40 (d, 2H, J=2.2);7.36 (m,2H); 7.22 (m, 4H);6.76 (d, 2H, J=8.5); 4.67 (s, 4H); 4.26 (q,4H, J=7.15); 2.87 (t, 4H); 1.95 (pent, 4H); 1.29 (t, 6H, J=7.15).

[0769] General Procedure D:

[0770] Step A:

[0771] The above diethyl ester (2.2 g, 2.9 mmol) was dissolved in 50 mLethanol, 20% solution of sodium hydroxide (5 mL) was added and themixture was left to stand for 48 h. The solvents were evaporated, theresidue dissolved in water and the product precipitated with HCl: Thesolid was filtered with suction, washed with water and dried yielding1.95 g (96%) of the title compound which was recrystallized fromdioxane/water to give 1.44 g of the solvate with ½ mol dioxane.

[0772] M.p. 181.5-184.5° C. R_(F) (free acid, SiO₂, ethyl acetate) 0.53.

[0773]¹H NMR spectrum (300 MHz, DMSO-d₆): 13.10 (s, 2 H); 7.52 (d, J=8.2Hz, 4 H); 7.41 (d, J=2.2 Hz, 2 H); 7.26 (dd, J=2.2 and 8.8 Hz, 2 H);7.22 (d, J=8.2 Hz, 4 H); 6.97 (d, J=8.8 Hz, 2 H); 4.79 (s, 4 H); 2.88(t, J=7.15 Hz, 4 H); 2.69 (t, J=7.15 Hz, 4 H); 1.80 (p, 4 H); dioxane3.55 (s).

Example 41 General Procedure B[4-(3-{4′-[3-(4-Carboxymethoxy-3-methoxy-phenylsulfanyl)-propyl]-biphenyl-4-yl}-propylsulfanyl)-2-methoxy-phenoxy]-aceticacid

[0774]

[0775] Step B:

[0776] A mixture of methyl 4-mercapto-2-methoxyphenoxyacetate(Intermediate 15) (1.6 g,7 mmol), 4,4′-biphenyidipropanolbismethanesulfonate (example 38)(1.48 g,3.5 mmol), potassium carbonate(1.38 g, 10 mmol) and 2-butanone (40 mL) was refluxed under stirring for8 h. Water and ethyl acetate were added, organic phase was separated,dried (K₂CO₃) and evaporated. The residue was purified by chromatographyon silica gel (25 g, ethyl acetate) and then recrystallized from diethylether yielding 1.60 g (66%) of the dimethyl ester of the title compound.

[0777] M.p.108.5-110.5° C.

[0778]¹H-NMR spectrum (DMSO): 7.51 (d, J=8.0 Hz, 4 H); 7.22 (d, J=8.0Hz, 4 H); 6.93 (s, 2 H); 6.82 (m, 4 H); 4.73 (s, 4 H); 3.73 (s, 6 H);3.66 (s, 6 H); 2.88 (t, 4 H); 2.70 (t, 4 H); 1.82 (m, 4 H).

[0779] General Procedure D:

[0780] Step A:

[0781] The above dimethyl ester (1.52 g, 2.2 mmol) was dissolved in themixture of ethanol (25 mL) and tetrahydrofuran (25 mL) under reflux, 20%solution of sodium hydroxide (3 mL)) was added and the mixture was leftto stand at laboratory temperature for 48 h. The solvents wereevaporated, water was added to the residue and the product wasprecipitated with HCl. The solid was filtered with suction, washed withwater and dried yielding 1.45 g (95%) of the title compound assesquihydrate.

[0782] M.p. 178-180° C. R_(F)(free acid, SiO₂, ethyl acetate) 0.50.

[0783]¹H NMR spectrum (300 MHz, DMSO-d₆): 13.0 (bs, 2 H); 7.51 (d, J=8.2Hz, 4 H); 7.22 (d, J=8.2 Hz, 4 H); 6.93 (d, J=1.8 Hz, 2 H); 6.85 (dd,J=1.8 and 8.4 Hz, 2 H); 6.78 (d, J=8.4 Hz, 2 H); 4.60 (s, 4 H); 3.73 (s,6 H); 2.88 (t, J=7.3 Hz, 4 H); 2.70 (t, J=7.3 Hz, 4 H); 1.81 (p, 4 H).

Example 42 General Procedure B{4-[3-(4-{4-[3-(4-Carboxymethoxy-3-trifluoromethyl-phenylsulfanyl)-propyl]-2-trifluoromethyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-propylsulfanyl]-2-trifluoromethyl-phenoxy)-aceticacid

[0784]

[0785] Step A:

[0786] To the solution of3-{4-[4-(3-hydroxy-propyl)-2-trifluoromethyl-phenylsulfanyl]-3-trifluoromethyl-phenyl}-propan-1-ol(intermediate 16) (4.0 g, 9.1 mmol) and triethylamine (2.5 g, 24.7 mmol)in dichloromethane (50 mL) methanesulfonyl chloride (2.5 g, 21.8 mmol)was added dropwise. The mixture was stirred overnight at roomtemperature, then washed with water and dichloromethane was evaporated.This afforded 5.4 g (99.5%) of methanesulfonic acid3-{4-[4-(3-methanesulfonyloxy-propyl)-2-trifluoromethyl-phenylsulfanyl]-3-trifluoromethyl-phenyl}-propylester as an oil.

[0787]¹H NMR spectrum (300 MHz, CDCl₃): 7.54 (s, 2 H); 7.25 (dd, J=1.1and 7.15 Hz, 2 H); 7.14 (d, J=8.0 Hz, 2 H); 4.23 (t, J=6.2 Hz, 4 H);3.00 (s, 6 H); 2.79 (t, J=7.0 Hz, 4 H); 2.07 (m, 4 H).

[0788] Step B:

[0789] The 4,4′-dithiobis-(2-trifluoromethylphenoxyacetic acid diethylester) (intermediate 11) (2.6 g, 4.65 mmol) was dissolved in 15 mLdimethylacetamide, sodium borohydride (0.4 g, 10.6 mmol) was addedportionwise at 5° C. and the mixture was stirred for 30 min. Thesolution of above bismethanesulfonate (2.3 g, 3.87 mmol) in acetone (30mL) and potassium carbonate (1.4 9, 10 mmol) were added and the mixturewas stirred overnight at ambient temperature and then refluxed for 7 h.Water and benzene were added, the organic layer was dried (K₂CO₃),filtered and evaporated to give a residue which was purified bychromatography on silica gel (100 g, benzene). This afforded 3.1 g (85%)of diethyl ester of the title compound.

[0790]¹H NMR spectrum (300 MHz, CDCl₃): 7.59 (d, 2H, J=2.2); 7.50 (d,2H, J=1.5); 7.45 (dd, 2H, J=2.2;8.5); 7.19 (dd, 2H, J=1.5;8.0); 7.11 (d,2H, J=8.0); 6.80 (d, 2H, J=8.5); 4.70 (S, 4H); 4.25 (q, 4H, J=7.15);2.84 (t, 4H, J=7.15); 2.76 (t, 4H, J=7.15); 1.89 (pent, 4H); 1.27 (t,6H, J=7.15)

[0791] General Procedure D:

[0792] Step A:

[0793] The above diethyl ester (3.0 g, 3.3 mmol) was dissolved in 100 mLethanol, 20% NaOH (5 mL) was added and the mixture was refluxed for 5 h.The solvent was evaporated, the residue dissolved in water and theproduct precipitated with conc. hydrochloric acid and extracted withchloroform. The organic layer was dried (MgSO₄), filtered and evaporatedaffording a residue which was purified by chromatography on silica gel(30 g, chloroform/ethanol 95:5). The yield of the title compound was1.82g (61%).

[0794] M.p. 58-64° C. R_(F) (SiO₂, ethyl acetate): 0.62

[0795]¹H NMR spectrum (300 MHz, DMSO-d₆): 7.60 (d, J=2.2 Hz, 2 H); 7.50(d, J=1.6 Hz, 2 H); 7.43 (dd, J=8.5 and 2.2 Hz, 2 H); 7.17 (dd, J=8.0and 1.6 Hz, 2 H); 7.11 (d, J=8.0 Hz, 2 H); 6.81 (d, J=8.5 Hz, 2 H); 4.76(s, 4 H); 2.85 (t, J=7.15 Hz, 4 H); 2.76 (t, J=7.15 Hz, 4 H); 1.89 (m, 4H).

[0796] Using a combination of the above methods, or methods analogoushereof, various compounds may be made within the scope of the presentinvention.

[0797] Pharmacological Methods

[0798] In vitro PPARalpha, PPARgamma and PPARdelta Activation Activity

[0799] The PPAR transient transactivation assays are based on transienttransfection into human HEK293 cells of two plasmids encoding a chimerictest protein and a reporter protein respectively. The chimeric testprotein is a fusion of the DNA binding domain (DBD) from the yeast GAL4transcription factor to the ligand binding domain (LBD) of the humanPPAR proteins. The PPAR-LBD moiety harbored in addition to the ligandbinding pocket also the native activation domain (activating function2=AF2) allowing the fusion protein to function as a PPAR liganddependent transcription factor. The GAL4 DBD will direct the chimericprotein to bind only to Gal4 enhancers (of which none existed in HEK293cells). The reporter plasmid contained a Gal4 enhancer driving theexpression of the firefly luciferase protein. After transfection, HEK293cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion proteinwill in turn bind to the Gal4 enhancer controlling the luciferaseexpression, and do nothing in the absence of ligand. Upon addition tothe cells of a PPAR ligand luciferase protein will be produced inamounts corresponding to the activation of the PPAR protein. The amountof luciferase protein is measured by light emission after addition ofthe appropriate substrate.

[0800] Cell Culture and Transfection

[0801] HEK293 cells were grown in DMEM+10% FCS. Cells were seededin96-well plates the day before transfection to give a confluency of50-80% at transfection. A total of 0,8 μg DNA containing 0,64 μgpM1α/γLBD, 0,1 μg pCMVβGal, 0,08 μg pGL2(Gal4)₅ and 0,02 μg pADVANTAGEwas transfected per well using FuGene transfection reagent according tothe manufacturers instructions (Roche). Cells were allowed to expressprotein for 48 h followed by addition of compound.

[0802] Plasmids: Human PPAR α, γ and δ was obtained by PCR amplificationusing cDNA synthesized by reverse transcription of mRNA from humanliver, adipose tissue and plancenta respectively. Amplified cDNAs werecloned into pCR2.1 and sequenced. The ligand binding domain (LBD) ofeach PPAR isoform was generated by PCR (PPARα: aa 167-C-terminus; PPARγ:aa 165-C-terminus; PPARδ: aa 128-C-terminus) and fused to the DNAbinding domain (DBD) of the yeast transcription factor GAL4 bysubcloning fragments in frame into the vector pM1 (Sadowski et al.(1992), Gene 118, 137) generating the plasmids pM1αLBD, pM1γLBD andpM1δ. Ensuing fusions were verified by sequencing. The reporter wasconstructed by inserting an oligonucleotide encoding five repeats of theGAL4 recognition sequence (5× CGGAGTACTGTCCTCCG(AG)) (Webster et al.(1988), Nucleic Acids Res. 16, 8192) into the vector pGL2 promotor(Promega) generating the plasmid pGL2(GAL4)₅. pCMVβGal was purchasedfrom Clontech and pADVANTAGE was purchased from Promega.

[0803] In Vitro Transactivation Assay

[0804] Compounds: All compounds were dissolved in DMSO and diluted1:1000 upon addition to the cells. Compounds were tested in quadruple inconcentrations ranging from 0.001 to 300 μM. Cells were treated withcompound for 24 h followed by luciferase assay. Each compound was testedin at least two separate experiments.

[0805] Luciferase assay: Medium including test compound was aspiratedand 100 μl PBS incl. 1 mM Mg++ and Ca++ was added to each well. Theluciferase assay was performed using the LucLite kit according to themanufacturers instructions (Packard Instruments). Light emission wasquantified by counting on a Packard LumiCounter. To measureβ-galactosidase activity 25 μl supernatant from each transfection lysatewas transferred to a new microplate. 0-galactosidase assays wereperformed in the microwell plates using a kit from Promega and read in aLabsystems Ascent Multiscan reader. The β-galactosidase data were usedto normalize (transfection efficiency, cell growth etc.) the luciferasedata.

[0806] Statistical Methods

[0807] The activity of a compound is calculated as fold inductioncompared to an untreated sample. For each compound the efficacy (maximalactivity) is given as a relative activity compared to to Wy14,643 forPPARα, Rosiglitazone for PPARγ and Carbacyclin for PPARδ. The EC50 isthe concentration giving 50% of maximal observed activity. EC50 valueswere calculated via non-linear regression using GraphPad PRISM 3.02(GraphPad Software, San Diego, Calif.). The results were expressed asmeans±SD.

1. A compound of the general formula (I):

wherein A is C₁₋₃-alkylene which is optionally substituted with one ormore substituents selected from halogen or C₁₋₃-alkyl, C₁₋₆alkoxy,C₃₋₆-cycloalkoxy, C₁₋₆alkylthio, C₃₋₆-cycloalkylthio or aralkoxy each ofwhich is optionally substituted with one or more halogens; orNR₁R₂wherein R₁ represents hydrogen or C₁₋₃-alkyl and R₂ represents—R₃—(C═O)—R₄ wherein: R₃ represents C₁₋₆-alkylene, C₂₋₆-alkenylene,C₄₋₆-cycloalkylene, C₄₋₆-cycloalkenylene, or arylene optionallysubstituted with one or more halogens; R₄ represents aryl optionallysubstituted with one or more halogens; or A is —O-A′ or —S-A′ wherein—O— or —S— is linked to X in formula (I) and wherein A′ is C₁₋₃-alkylenewhich is optionally substituted with one or more substituents selectedfrom halogen or C₁₋₃-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio or aralkoxy each of which isoptionally substituted with one or more halogens; or NR₁R₂ wherein R₁represents hydrogen or C₁₋₃-alkyl and R₂ represents —R₃—(C═O)—R₄wherein: R₃ represents C₁₋₆-alkylene, C₂₋₆-alkenylene,C₄₋₆-cycloalkylene, C₄₋₆-cycloalkenylene, or arylene optionallysubstituted with one or more halogens; R₄ represents aryl optionallysubstituted with one or more halogens; and B is C₁₋₃-alkylene which isoptionally substituted with one or more substituents selected fromhalogen or C₁₋₃-alkyl, C₁₋₆alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆alkylthio,C₃₋₆-cycloalkylthio or aralkoxy each of which is optionally substitutedwith one or more halogens; or NR₁R₂ wherein R₁ represents hydrogen orC₁₋₃-alkyl and R₂ represents —R₃—(C═O)—R₄ wherein: R₃ representsC₁₋₆alkylene, C₂₋₆-alkenylene, C₄₋₆-cycloalkylene, C₄₋₆-cycloalkenylene,or arylene optionally substituted with one or more halogens; R₄represents aryl optionally substituted with one or more halogens; or Bis —O— B′ or —S—B′ wherein —O— or —S— is linked to Y in formula (I) andwherein B′ is C₁₋₃-alkylene which is optionally substituted with one ormore substituents selected from halogen or C₁₋₃-alkyl, C₁₋₆-alkoxy,C₃₋₆-cycloalkoxy, C₁₋₆alkylthio, C₃₋₆-cycloalkylthio or aralkoxy each ofwhich is optionally substituted with one or more halogens; orNR₁R₂wherein R₁ represents hydrogen or C₁₋₃-alkyl and R₂ represents—R₃—(C═O)—R₄ wherein: R₃ represents C₁₋₆-alkylene, C₂₋₆-alkenylene,C₄₋₆-cycloalkylene, C₄₋₆-cycloalkenylene, or arylene optionallysubstituted with one or more halogens; R₄ represents aryl optionallysubstituted with one or more halogens; and D is H, C₁₋₆alkyl orC₃4-cycloalkyl; and E is H, C₁₋₆alkyl or C₃4-cycloalkyl; and L and M areindependently —O— or —S—; and T is C₁₋₆divalent saturated carbon chainoptionally substituted with one or more substituents selected fromhalogen or hydroxy; or aryl, aralkoxy or C₁₋₃-alkoxy which is optionallysubstituted with halogen; or T is —NR₁-T′ wherein —NR₁— is linked to Zin formula (I) and wherein T′ is C₁₋₆ alkylene which is optionallysubstituted with one or more halogen and R₁ represents hydrogen or C₁₋₃alkyl; and U is C₁₋₆ divalent saturated carbon chain optionallysubstituted with one or more substituents selected from halogen orhydroxy; or aryl, aralkoxy or C₁₋₃-alkoxy which is optionallysubstituted with halogen; or U is —NR₁—U′ wherein —NR₁— is linked to Zin formula (I) and wherein U′ is C₁₋₆ alkylene which is optionallysubstituted with one or more halogen and R₁ represents hydrogen or C₁₋₃alkyl; and X is arylene or heteroarylene each of which is optionallysubstituted with one or more substituents selected from halogen orhydroxy; or C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,C₁₋₆alkylthio, C₃₋₆-cycloalkylthio, aryl, aralkyl each of which isoptionally substituted with one or more halogens; or Y is arylene orheteroarylene each of which is optionally substituted with one or moresubstituents selected from halogen or hydroxy; or C₁₋₆-alkyl,C₃₋₆-cycloalkyl, C₁₋₆alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆alkylthio,C₃₋₆-cycloalkylthio aryl, aralkyl each of which is optionallysubstituted with one or more halogens; or Z is arylene, heteroarylene ora divalent polycyclic ringsystem each of which is optionally substitutedwith one or more substituents selected from halogen, oxo or hydroxy; orC₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,C₁₋₆alkylthio, C₃₋₆-cycloalkylthio each of which is optionallysubstituted with one or more halogen; or a pharmaceutically acceptablesalt thereof, or a pharmaceutically acceptable solvate thereof, or anytautomeric forms, stereoisomers, mixture of stereoisomers, racemicmixture, or polymorphs.
 2. A compound according to claim 1 wherein A isC₁₋₃-alkylene, which is optionally substituted with one or moresubstituents selected from methyl, C₁₋₃-alkoxy, C₃₋₆-cycloalkoxy orbenzyloxy each of which is optionally substituted with one or morehalogens; or NR₁R₂ wherein R₁ represents hydrogen and R₂ represents—R₃—(C═O)—R₄ wherein: R₃ represents C₁₋₆-alkylene, C₂₋₆-alkenylene,C₄₋₆-cycloalkylene, C₄₋₆-cycloalkenylene, or phenylene optionallysubstituted with one or more halogens; R₄ represents phenyl optionallysubstituted with one or more halogens.
 3. A compound according to claim2 wherein A is methylene or ethylene each of which is optionallysubstituted with one or more substituents selected from methoxy orethoxy; or NR₁R₂ wherein R₁ represents hydrogen and R₂ represents—R₃—(C═O)—R₄ wherein R₃ and R₄ represents phenyl.
 4. A compoundaccording to claim 2 wherein A is ethylene which is optionallysubstituted with ethoxy.
 5. A compound according to claim 1 wherein A is—O-A′ or —S-A′ wherein —O— or —S— is linked to X in formula (I) andwherein A′ is C₁₋₃-alkylene which is optionally substituted with one ormore substituents selected from halogen or C₁₋₃-alkyl, C₁₋₆alkoxy,C₃₋₆-cycloalkoxy or aralkoxy each of which is optionally substitutedwith halogen.
 6. A compound according to claim 5 wherein A is —O-A′ or—S-A′ wherein —O— or —S— is linked to X in formula (I) and wherein A′ ismethylene or ethylene each of which is optionally substituted with oneor more substituents selected from methyl, methoxy or ethoxy.
 7. Acompound according to claim 6 wherein A is —O-A′ wherein —O— is linkedto X in formula (I) and wherein A′ is methylene or ethylene.
 8. Acompound according to claim 7 wherein A is —O-A′ wherein —O— is linkedto X in formula (I) and wherein A′ is methylene.
 9. A compound accordingto claim 1 wherein B is C₁₋₃-alkylene, which is optionally substitutedwith one or more substituents selected from methyl, C₁₋₃-alkoxy,C₃₋₆-cycloalkoxy or benzyloxy each of which is optionally substitutedwith one or more halogens; or NR₁R₂ wherein R₁ represents hydrogen andR₂ represents —R₃—(C═O)—R₄ wherein: R₃ represents C₁₋₆-alkylene,C₂₋₆-alkenylene, C₄₋₆-cycloalkylene, C₄₋₆-cycloalkenylene, or phenyleneoptionally substituted with one or more halogens; R₄ represents phenyloptionally substituted with one or more halogens.
 10. A compoundaccording to claim 9 wherein B is methylene or ethylene each of which isoptionally substituted with one or more substituents selected frommethoxy or ethoxy; or NR₁R₂ wherein R₁ represents hydrogen and R₂represents —R₃—(C═O)—R₄ wherein R₃ and R₄ represents phenyl.
 11. Acompound according to claim 9 wherein B is ethylene which is optionallysubstituted with ethoxy.
 12. A compound according to claim 1 wherein Bis —O— B′ or —S—B′ wherein —O— or —S— is linked to Y in formula (I) andwherein B′ is C₁₋₃-alkylene which is optionally substituted with one ormore substituents selected from halogen or C₁₋₃-alkyl, C₁₋₆alkoxy,C₃₋₆-cycloalkoxy or aralkoxy each of which is optionally substitutedwith halogen.
 13. A compound according to claim 12 wherein B is —O— B′or —S—B′ wherein —O— or —S— is linked to Y in formula (I) and wherein B′is methylene or ethylene each of which is optionally substituted withone or more substituents selected from methyl, methoxy or ethoxy.
 14. Acompound according to claim 13 wherein B is —O— B′ wherein —O— is linkedto Y in formula (I) and wherein B′ is methylene or ethylene.
 15. Acompound according to claim 14 wherein B is —O— B′ wherein —O— is linkedto Y in formula (I) and wherein B′ is methylene.
 16. A compoundaccording to claim 1 wherein D is H.
 17. A compound according to claim 1wherein D is methyl or ethyl.
 18. A compound according to claim 1wherein D is isopropyl.
 19. A compound according to claim 1 wherein E isH.
 20. A compound according to claim 1 wherein E is methyl or ethyl. 21.A compound according to claim 1 wherein E is isopropyl.
 22. A compoundaccording to claim 1 wherein L is —O—.
 23. A compound according to claim1 wherein L is —S—.
 24. A compound according to claim 1 wherein M is—O—.
 25. A compound according to claim 1 wherein M is —S—.
 26. Acompound according to claim 1 wherein T is C₁₋₆divalent saturated carbonchain optionally substituted with one or more substituents selected fromphenyl, benzyloxy or C₁₋₃-alkoxy which is optionally substituted withhalogen.
 27. A compound according to claim 26 wherein T is anunsubstituted C₁₋₆ divalent saturated carbon chain.
 28. A compoundaccording to claim 27 wherein T is ethylene or propylene.
 29. A compoundaccording to claim 1 wherein T is —NR₁-T′ wherein —NR₁— is linked to Zin formula (I) and wherein T′ is C₁₋₆ alkylene which is optionallysubstituted with one or more halogen and R₁ represents hydrogen or C₁₋₃alkyl.
 30. A compound according to claim 29 wherein T is —NR₁-T′ wherein-NR₁— is linked to Z in formula (I) and wherein T′ is C₁₋₃ alkylene andR₁ represents hydrogen or C₁₋₃ alkyl.
 31. A compound according to claim30 wherein T is —NR₁-T′ wherein —NR₁— is linked to Z in formula (I) andwherein T′ is ethylene and R₁ is methyl.
 32. A compound according toclaim 1 wherein U is C₁₋₆ divalent saturated carbon chain optionallysubstituted with one or more substituents selected from phenyl,benzyloxy or C₁₋₃-alkoxy which is optionally substituted with halogen.33. A compound according to claim 32 wherein U is an unsubstitutedC₁₋₆divalent saturated carbon chain.
 34. A compound according to claim33 wherein U is ethylene or propylene.
 35. A compound according to claim1 wherein U is —NR₁—U′ wherein —NR₁— is linked to Z in formula (I) andwherein U′ is C₁₋₆ alkylene which is optionally substituted with one ormore halogen and R₁ represents hydrogen or C₁₋₃ alkyl.
 36. A compoundaccording to claim 35 wherein U is —NR₁—U′ wherein —NR₁— is linked to Zin formula (I) and wherein U′ is C₁₃ alkylene and R₁ represents hydrogenor C₁ ₃ alkyl.
 37. A compound according to claim 36 wherein U is —NR₁—U′wherein —NR₁— is linked to Z in formula (I) and wherein U′ is ethyleneand R₁ is methyl.
 38. A compound according to claim 1 wherein X isarylene or heteroarylene each of which is optionally substituted withone or more substituents selected from halogen; or C₁₋₆alkyl,C₁₋₆-alkoxy, aryl each of which is optionally substituted with one ormore halogen.
 39. A compound according to claim 38 wherein X is aryleneoptionally substituted with one or more substituents selected fromhalogen; or C₁₋₆-alkyl, C₁₋₆-alkoxy, aryl each of which is optionallysubstituted with one or more halogen.
 40. A compound according to claim39 wherein X is phenylene optionally substituted with one or moresubstituents selected from halogen; or C₁₋₃-alkyl, C₁₋₃-alkoxy, phenyleach of which is optionally substituted with one or more halogen.
 41. Acompound according to claim 40 wherein X is phenylene optionallysubstituted with one or more halogen, methyl or phenyl.
 42. A compoundaccording to claim 40 wherein X is phenylene optionally substituted withone or more trifluoromethyl or methoxy.
 43. A compound according toclaim 1 wherein Y is arylene or heteroarylene each of which isoptionally substituted with one or more substituents selected fromhalogen; or C₁₋₆-alkyl, C₁₋₆-alkoxy, aryl each of which is optionallysubstituted with one or more halogen.
 44. A compound according to claim43 wherein Y is arylene optionally substituted with one or moresubstituents selected from halogen; or C₁₋₆-alkyl, C₁₋₆-alkoxy, aryleach of which is optionally substituted with one or more halogen.
 45. Acompound according to claim 44 wherein Y is phenylene optionallysubstituted with one or more substituents selected from halogen; orC₁₋₃-alkyl, C₁₋₃-alkoxy, phenyl each of which is optionally substitutedwith one or more halogen.
 46. A compound according to claim 45 wherein Yis phenylene optionally substituted with one or more halogen, methyl orphenyl.
 47. A compound according to claim 45 wherein Y is phenyleneoptionally substituted with one or more trifluoromethyl or methoxy. 48.A compound according to claim 1 wherein Z is arylene, heteroarylene or adivalent polycyclic ringsystem each of which is optionally substitutedwith one or more substituents selected from halogen, oxo; or C₁₋₆-alkyl,C₁₋₆-alkoxy each of which is optionally substituted with one or morehalogen.
 49. A compound according to claims 48 wherein Z is selectedamong the following groups:

each of which is optionally substituted with one or more substituentsselected from halogen; or C₁₋₆alkyl or C₁₋₆alkoxy each of which isoptionally substituted with one or more halogen.
 50. A compoundaccording to claim 49 wherein Z is selected among the following groups:

each of which is optionally substituted with one or more substituentsselected from halogen; or C₁₋₆-alkyl or C₁₋₆-alkoxy each of which isoptionally substituted with one or more halogen.
 51. A compoundaccording to claim 50 wherein Z is selected among the following groups:

each of which is optionally substituted with one or more substituentsselected from halogen; or C₁₋₆alkyl or C₁₋₆alkoxy each of which isoptionally substituted with one or more halogen.
 52. A compoundaccording to claim 51 wherein Z is selected among the following groups:

each of which is optionally substituted with one or more substituentsselected from halogen; or C₁₋₆-alkyl or C₁₋₆alkoxy each of which isoptionally substituted with one or more halogen.
 53. A compoundaccording to claim 52 wherein Z is:


54. A compound according to claim 52 wherein Z is:

which is optionally substituted with one or more of trifluoromethyl. 55.A compound according to claim 52 wherein Z is:


56. A compound according to claim 51 wherein Z is:


57. A compound according to claim 51 wherein Z is:


58. The compound according to claim 1 which is selected from thefollowing group:2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-methoxycarbonyl-ethyl)-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-phenyl]-propionicacid;3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-2-chloro-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-3-chloro-phenyl]-2-ethoxy-propionicacid;(5′-{2-[(6-{[2-(2′-Ethoxycarbonylmethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid;(5′-{2-[(6-{[2-(2′-Carboxymethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid;(S,S)-2-(2-Benzoyl-phenylamino)-3-(4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-methoxy-carbonyl-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)ethoxy]-phenyl}-propionicacid;(S,S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-carboxy-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-propionicacid;(3-Chloro-4-{2-[(6-{[2-(2-chloro-4-ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid;(4-{2-[(6-{[2-(4-Carboxymethyl-2-chloro-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-3-chloro-phenyl)-aceticacid;(3-{2-[(6-{[2-(3-Ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid;(3-{2-[(6-{[2-(3-Carboxymethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid;(S,S)-2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-propionicacid;(S,S)-3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-2-ethoxy-propionicacid;(S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid;(S,S)-3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;(S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid;(S,S)-3-4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;(S,S)-3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid isopropyl ester;(S,S)-3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;(S,S)-2-Ethoxy-3-{4-[3-(7-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-propionicacid isopropyl ester;(S,S)-3-{4-[3-(7-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxyl]-phenyl}-2-ethoxy-propionicacid;[4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoro-methyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoro-methyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;[4-(3-{7-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;[4-(3-{7-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl)-propyl-sulfanyl)-2-methyl-phenoxy]-aceticacid;(4-{2-[2-(3-{4-[2-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;(4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;(S,S)-2-Ethoxy-3-[4-(2-{2-[4′-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid;(S,S)-3-[4-(2-{2-[4′-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid;(S,S)-2-Ethoxy-3-[4-(2-{2-[3-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid; and(S,S)-3-[4-(2-{2-[3-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid; or a salt thereof with a pharmaceutically acceptable acid or base,or any optical isomer or mixture of optical isomers, racemic mixture, orany tautomeric forms.
 59. The compound according to claim 1 which isselected from the following group:2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-methoxycarbonyl-ethyl)-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-phenyl]-propionicacid methyl ester;(5′-{2-[(6-{[2-(2′-Ethoxycarbonylmethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid ethyl ester;(S,S)-2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-methyloxy-carbonyl-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)ethoxy]-phenyl}-propionicacid methyl ester;(3-Chloro-4-{2-[(6-{[2-(2-chloro-4-ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid ethyl ester;(3-{2-[(6-{[2-(3-Ethoxycarbonylmethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid ethyl ester;(S,S)-2-Ethoxy-3-[4-(2-{[6-({2-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethoxy)-phenyl]-propionicacid ethyl ester;(S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid isopropyl ester;(S,S)-2-Ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionicacid isopropyl ester;(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl)-2-ethoxy-propionicacid isopropyl ester;(S,S)-3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid isopropyl ester;[4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoro-methyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester;[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoro-methyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid methyl ester;[4-(3-{7-[3-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propylsulfanyl)2-methyl-phenoxy]-aceticacid methyl ester;(4-{2-[2-(3-{4-[2-(4-Methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid methyl ester;(S,S)-2-Ethoxy-3-[4-(2-{2-[4′-(4-{2-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid isopropyl ester; and(S,S)-2-Ethoxy-3-[4-(2-{2-[3-(4-(2-[4-{2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl)-ethoxy)-phenyl]-propionicacid isopropyl ester; or a salt thereof with a pharmaceuticallyacceptable acid or base, or any optical isomer or mixture of opticalisomers, racemic mixture, or any tautomeric forms.
 60. The compoundaccording to claim 1 which is selected from the following group:[4-(3-{4′-[3-(4-Carboxymethylsulfanyl-3-chloro-phenylsulfanyl)-propyl]-3,3′-bis-rifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-chloro-phenylsulfanyl]-aceticacid;[4-[3-[4′-[3-(4-Carboxymethoxy-3-trifluoromethylphenylsulfanyl)propyl]biphenyl-4-yl]-propyl-sulfanyl]-2-trifluoromethylphenoxy]aceticacid;[4-[3-[4′-[3-(4-Carboxymethoxy-3-chlorophenylsulfanyl)propyl]-3,3′-bis-trifluoromethylbiphenyl-4-yl]propylsulfanyl]-2-chlorophenoxy]aceticacid;[4-(3-{4′-[3-(4-Carboxymethoxy-3-chloro-phenylsulfanyl)-propyl]-biphenyl-4-yl)-propyl-sulfanyl)-2-chloro-phenoxy]-aceticacid; and[4-(3-{4′-[3-(4-Carboxymethoxy-3-methoxy-phenylsulfanyl)-propyl]-biphenyl-4-yl)-propyl-sulfanyl)-2-methoxy-phenoxy]-aceticacid; or a salt thereof with a pharmaceutically acceptable acid or base,or any optical isomer or mixture of optical isomers, racemic mixture, orany tautomeric forms.
 61. The compound according to claim 1 which isselected from the following group:3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-2yl-methyl-amino}-ethoxy)-phenyl]-2-ethoxy-propionicacid;(3-{2-[(6-{[2-(3-Carboxymethyl-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-aceticacid;2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-carboxy-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-propionicacid;(5′-{2-[(6-{[2-(2′-Carboxymethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-[1,1′;3′,1″]terphenyl-2′-yloxy)-aceticacid;3-[4-(2-{[6-({2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-ethyl}-methyl-amino)-pyridin-2-yl]-methyl-amino}-ethylsulfanyl)-phenyl]-2-ethoxy-propionicacid;(4-{2-[(6-{[2-(4-Carboxymethyl-2-chloro-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-3-chloro-phenyl)-aceticacid;(4-{2-[(6-{[2-(4-Carboxymethyl-2-bromo-phenoxy)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethoxy}-3-bromo-phenyl)-aceticacid;(4-{2-[(6-{[2-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;(4-{2-[(6-{[2-(4-Carboxymethoxy-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-phenoxy)-aceticacid;(3-{2-[(6-{[2-(3-Carboxymethyl-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-phenyl)-aceticacid;(4-{2-[(6-{[2-(4-Carboxymethyl-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-phenyl)-aceticacid;2-(2-Benzoyl-phenylamino)-3-{4-[2-({6-[(2-{4-[2-(2-benzoyl-phenylamino)-2-carboxy-ethyl]-phenylsulfanyl}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethylsulfanyl]-phenyl}-propionicacid;3-{4-[2-({6-[(2-{4-[2-Carboxy-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-ethyl]-phenyl-sulfanyl}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethylsulfanyl]-phenyl}-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionicacid;3-{4-[2-({6-[(2-{4-[2-Carboxy-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-ethyl]-phenoxy}-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethoxy]-phenyl}-2-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionicacid;(4-{2-[(6-{[2-(4-Carboxymethyl-2-chloro-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-3-chloro-phenyl)-aceticacid;(4-{2-[(6-{[2-(4-Carboxymethyl-2-bromo-phenylsulfanyl)-ethyl]-methyl-amino}-pyridin-2-yl)-methyl-amino]-ethylsulfanyl}-3-bromo-phenyl)-aceticacid;3-[4-(2-{2-[3-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethoxy)-phenyl]-2-ethoxy-propionicacid;(4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;(4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-3-methyl-phenoxy)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid;(4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-phenoxy)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-aceticacid;(4-{2-[2-(3-{4-[2-(4-Carboxymethoxy-phenylsulfanyl)-ethyl]-5-methyl-oxazol-2-yl}-phenyl)-5-methyl-oxazol-4-yl]-ethylsulfanyl}-phenoxy)-aceticacid;3-[4-(2-{2-[3-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-ethyl}-5-methyl-oxazol-2-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethylsulfanyl)-phenyl]-2-ethoxy-propionicacid;3-{4-[3-(7-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxyl]-phenyl}-2-ethoxy-propionicacid;3-{4-[3-(7-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-propyl}-9H-fluoren-2-yl)-propyl-sulfanyl]-phenyl}-2-ethoxy-propionicacid;[4-(3-{7-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propyl-sulfanyl)-2-methyl-phenoxy]-aceticacid;[4-(3-{7-[3-(4-Carboxymethoxy-phenylsulfanyl)-propyl]-9H-fluoren-2-yl}-propylsulfanyl)-phenoxy]-aceticacid;3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-9H-fluoren-2-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;3-{3-Bromo-4-[3-(7-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenylsulfanyl]-propyl}-9H-fluoren-2-yl)-propylsulfanyl]-phenyl}-2-ethoxy-propionicacid;3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;3-{4-[3-(4′-{3-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;3-{3-Bromo-4-[3-(4′-{3-[2-bromo-4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-propyl}-3,3′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-2-ethoxy-propionicacid;[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Carboxymethoxy-phenylsulfanyl)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Carboxymethoxy-phenoxy)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propoxy)-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenoxy)-propyl]-3,3′-bis-trifluoromethyl-biphenyl-4-yl}-propoxy)-2-methyl-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)2-methyl-phenoxy]-aceticacid;[4-(3-{4′-[3-(4-Carboxymethoxy-3-methyl-phenoxy)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propoxy)-2-methyl-phenoxy]-aceticacid; and3-[4-(2-{2-[4′-(4-{2-[4-(2-Carboxy-2-ethoxy-ethyl)-phenoxy]-ethyl}-5-methyl-oxazol-2-yl)-biphenyl-4-yl]-5-methyl-oxazol-4-yl}-ethoxy)-propionicacid; or a salt thereof with a pharmaceutically acceptable acid or base,or any optical isomer or mixture of optical isomers, racemic mixture, orany tautomeric forms.
 62. A compound which is{4-[3-(4-{4-[3-(4-Carboxymethoxy-3-trifluoromethyl-phenyl-sulfanyl)propyl]-2-trifluoromethyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-propylsulfanyl]-2-trifluoromethyl-phenoxy}-aceticacid or a salt thereof with a pharmaceutically acceptable acid or base,or any optical isomer or mixture of optical isomers, racemic mixture, orany tautomeric forms.
 63. A compound according to claim 1, which is aPPARδ agonist.
 64. A compound according to claim 63, which is aselective PPARδ agonist.
 65. A pharmaceutical composition comprising, asan active ingredient, at least one compound according to claim 1together with one or more pharmaceutically acceptable carriers orexcipients.
 66. A pharmaceutical composition according to claim 65 inunit dosage form, comprising from about 0.05 mg to about 1000 mg,preferably from about 0.1 to about 500 mg of and especially preferredfrom about 0.5 mg to about 200 mg per day of compound.
 67. Apharmaceutical composition for the treatment of conditions mediated bynuclear receptors, in particular the Peroxisome Proliferator-ActivatedReceptors (PPAR), the composition comprising a compound according toclaim 1 together with one or more pharmaceutically acceptable carriersor excipients.
 68. A pharmaceutical composition for the treatment oftype I diabetes, type II diabetes, dyslipidemia, syndrome X (includingthe metabolic syndrome, i.e. impaired glucose tolerance, insulinresistance, hypertrigyceridaemia and/or obesity), cardiovasculardiseases (including atherosclerosis) or hypercholesteremia comprising acompound according to claim 1 together with one or more pharmaceuticallyacceptable carriers or excipients.
 69. A pharmaceutical compositionaccording to claim 65 for oral, nasal, transdermal, pulmonal, orparenteral administration.
 70. A method for the treatment of conditionsmediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR), the method comprisingadministering to a subject in need thereof an effective amount of acompound according to claim 1 or a pharmaceutical composition comprisingthe same.
 71. A method for the treatment of type I diabetes, type 11diabetes, dyslipidemia, syndrome X (including the metabolic syndrome,i.e. impaired glucose tolerance, insulin resistance,hypertrigyceridaemia and/or obesity), cardiovascular diseases (includingatherosclerosis) or hypercholesteremia, the method comprisingadministering to a subject in need thereof an effective amount of acompound according to claim 1 or of a pharmaceutical compositioncomprising the same.
 72. The method according to claim 70 wherein theeffective amount of the compound is in the range of from about 0.05 mgto about 1000 mg, preferably from about 0.1 to about 500 mg of andespecially preferred from about 0.5 mg to about 200 mg per day.
 73. Themethod according to claim 71 wherein the effective amount of thecompound is in the range of from about 0.05 mg to about 1000 mg,preferably from about 0.1 to about 500 mg of and especially preferredfrom about 0.5 mg to about 200 mg per day.